Tetrahydrofuro[3,2-B] pyrrol-3-ones as cathepsin K inhibitors

ABSTRACT

The present invention relates to compounds of formula (I), and pharmaceutically acceptable salts thereof, 
                         
wherein:
     X is CH or N;   one of R 1  and R 2  is H, and the other is selected from OR 6 , SR 6 , NR 6 R 7 , N 3 , Me, Et, CF 3 , SOR 8  and SO 2 R 8 ;   R 3  is selected from tert-butylmethyl, iso-propylmethyl, sec-butyl, tert-butyl, cyclopentyl and cyclohexyl;   R 4  is optionally substituted C 1-8  alkyl or optionally substituted C 3-8  cycloalkyl;   R 6  and R 7  are each independently selected from H, C 1-8 -alkyl and C 3-8 -cycloalkyl, or R 6  and R 7  are linked to form a cyclic group together with the nitrogen to which they are attached; and   R 8  is C 1-8 -alkyl or C 3-8 -cycloalkyl.   
     The invention further relates to pharmaceutical compositions comprising compounds of formula (I), and the use of such compounds in the treatment of a disease selected from osteoporosis, Paget&#39;s disease, Chagas&#39;s disease, malaria, gingival diseases, hypercalaemia, metabolic bone disease, diseases involving matrix or cartilage degradation, and bone cancer disorders such as bone metastases and associated pain.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of PCT application no.PCT/GB2007/002642, filed Jul. 13, 2007, which claims priority to GBPatent Application No. 0614044.6, filed Jul. 14, 2006. The contents ofthese applications are incorporated herein by reference in theirentirety.

The present invention relates to compounds that are inhibitors ofcysteine proteinases, pharmaceutical compositions containing saidcompounds, and their use in therapy. More specifically, but notexclusively, the invention relates to compounds that are inhibitors ofcathepsin K and related cysteine proteinases of the CA clan. Suchcompounds are particularly useful for the in vivo therapeutic treatmentof diseases in which participation of a cysteine proteinase isimplicated.

BACKGROUND TO THE INVENTION

Proteinases form a substantial group of biological molecules which todate constitute approximately 2% of all the gene products identifiedfollowing analysis of several completed genome sequencing programmes.Proteinases have evolved to participate in an enormous range ofbiological processes, mediating their effect by cleavage of peptideamide bonds within the myriad of proteins found in nature. Thishydrolytic action is performed by initially recognising, then bindingto, particular three-dimensional electronic surfaces displayed by aprotein, which align the bond for cleavage precisely within theproteinase catalytic site. Catalytic hydrolysis then commences throughnucleophilic attack of the amide bond to be cleaved either via an aminoacid side-chain of the proteinase itself, or through the action of awater molecule that is bound to and activated by the proteinase.Proteinases in which the attacking nucleophile is the thiol side-chainof a Cys residue are known as cysteine proteinases. The generalclassification of ‘cysteine proteinase’ contains many members found in awide range of organisms from viruses, bacteria, protozoa, plants andfungi to mammals.

Cathepsin K and indeed many other crucial proteinases belong to thepapain-like CAC1 family. Cysteine proteinases are classified into‘clans’ based upon a similarity in the three-dimensional structure or aconserved arrangement of catalytic residues within the proteinaseprimary sequence. Additionally, ‘clans’ may be further classified into‘families’ in which each proteinase shares a statistically significantrelationship with other members when comparing the portions of aminoacid sequence which constitute the parts responsible for the proteinaseactivity (see Barrett, A. J et al, in ‘Handbook of Proteolytic Enzymes’,Eds. Barrett, A. J., Rawlings, N. D., and Woessner, J. F. Publ. AcademicPress, 1998, for a thorough discussion).

To date, cysteine proteinases have been classified into five clans, CA,CB, CC, CD and CE (Barrett, A. J. et al, 1998). A proteinase from thetropical papaya fruit ‘papain’ forms the foundation of clan CA, whichcurrently contains over 80 distinct and complete entries in varioussequence databases, with many more expected from the current genomesequencing efforts. Proteinases of clan CA/family C1 have beenimplicated in a multitude of house-keeping roles and disease processes.e.g. human proteinases such as cathepsin K (osteoporosis,osteoarthritis), cathepsin S (multiple sclerosis, rheumatoid arthritis,autoimmune disorders), cathepsin L (metastases), cathepsin B(metastases, arthritis), cathepsin F (antigen processing), cathepsin V(T-cell selection), dipeptidyl peptidase I (granulocyte serineproteinase activation) or parasitic proteinases such as falcipain(malaria parasite Plasmodium falciparum) and cruzipain (Trypanosomacruzi infection). Recently a bacterial proteinase, staphylopain (S.aureus infection) has also been tentatively assigned to clan CA.

X-ray crystallographic structures are available for a range of the abovementioned proteinases in complex with a range of inhibitors e.g. papain(PDB entries, 1pad, 1pe6, 1pip, 1pop, 4pad, 5pad, 6pad, 1ppp, 1the,1csb, 1huc), cathepsin K (1au0, 1au2, 1au3, 1au4, 1atk, 1mem, 1bgo,1ayw, 1ayu, 1nl6, 1nlj, 1q6k, 1snk, 1tu6), cathepsin L (1cs8, 1mhw),cathepsin S (1glo, 1ms6, 1npz), cathepsin V (1fh0), dipeptidyl peptidaseI (1jqp, 1k3b), cathepsin B (1gmy, 1csb), cathepsin F (1m6d), cruzain (arecombinant form of cruzipain see Eakin, A. E. et al, 268(9), 6115-6118,1993) (1ewp, 1aim, 2aim, 1F29, 1F2A, 1F2B, 1F2C), staphylopain (1cv8).Each of the structures displays a similar overall active-site topology,as would be expected by their ‘clan’ and ‘family’ classification andsuch structural similarity exemplifies one aspect of the difficultiesinvolved in discovering a selective inhibitor of cathepsin K suitablefor human use. However, subtle differences in terms of the depth andintricate shape of the active site groove of each CAC1 proteinase areevident, which may be exploited for selective inhibitor design.Additionally, many of the current substrate-based inhibitor complexes ofCAC1 family proteinases show a series of conserved hydrogen bondsbetween the inhibitor and the proteinase backbone, which contributesignificantly to inhibitor potency. Primarily a bidentate hydrogen-bondis observed between the proteinase Gly66 (C═O)/inhibitor N—H and theproteinase Gly66(NH)/inhibitor (C═O), where the inhibitor (C═O) and (NH)are provided by an amino acid residue NHCHRCO that constitutes the S2sub-site binding element within the inhibitor (see Berger, A. andSchecter, I. Philos. Trans. R. Soc. Lond. [Biol.], 257, 249-264, 1970for a description of proteinase binding site nomenclature). A furtherhydrogen-bond between the proteinase main-chain (C═O) of asparagine oraspartic acid (158 to 163, residue number varies between proteinases)and an inhibitor (N—H) is often observed, where the inhibitor (N—H) isprovided by the S1 sub-site binding element within the inhibitor. Thus,the motif X—NHCHRCO—NH—Y is widely observed amongst the prior artsubstrate-based inhibitors of CAC1 proteinases.

Cathepsin K is thought to be significant in diseases involving excessiveloss of bone or cartilage. Bone consists of a protein matrixincorporating hydroxyapatite crystals. About 90% of the structuralprotein of the matrix is type I collagen, with the remainder comprisingvarious non-collagenous proteins such as osteocalcin, proteoglycans,osteopontin, osteonectin, thrombospondin, fibronectin and bonesialoprotein.

Skeletal bone is not a static structure but continually undergoes acycle of bone resorption and replacement. Bone resorption is carried outby osteoclasts, which are multinuclear cells of haematopoietic lineage.Osteoclasts adhere to the bone surface and form a tight sealing zone.The membrane on the apical surface of the osteoclasts is folded so as tocreate a closed extracellular compartment between the osteoclast and thebone surface, which is acidified by proton pumps in the osteoclastmembrane. Proteolytic enzymes are secreted into the compartment from theosteoclast. The high acidity in the compartment causes thehydroxyapatite at the surface of the bone to be dissolved and theproteolytic enzymes break down the protein matrix causing a resorptionlacuna to be formed. Following bone resorption, osteoblasts produce anew protein matrix that is subsequently mineralised.

In disease states such as osteoporosis and Paget's disease, the boneresorption and replacement cycle is disrupted leading to a net loss ofbone with each cycle. This leads to weakening of the bone and thereforeto increased risk of bone fracture.

Cathepsin K is expressed at a high level in osteoclasts and is thereforethought to be essential for bone resorption. Thus, selective inhibitionof cathepsin K is likely to be effective in the treatment of diseasesinvolving excessive bone loss. These include osteoporosis, gingivaldiseases such as gingivitis and periodontitis, Paget's disease,hypercalaemia of malignancy and metabolic bone disease.

In addition to osteoclasts, high levels of cathepsin K are also found inchondroclasts from the synovium of osteoarthritic patients. It thereforeappears that cathepsin K inhibitors will be of use in the treatment ofdiseases involving matrix or cartilage degradation, in particularosteoarthritis and rheumatoid arthritis.

Elevated levels of cathepsin K are also found in metastatic neoplasticcells which suggests that cathepsin K inhibitors may also be useful fortreating certain neoplastic diseases.

In the prior art, the development of cysteine proteinase inhibitors forhuman use has recently been an area of intense activity (e.g. seeDeaton, D. N. and Kumar, S., Prog. Med. Chem. 42, 245-375, 2004; Bromme,D. and Kaleta, J., Curr. Pharm. Des., 8, 1639-1658, 2002; Kim, W. andKang, K., Expert Opin. Ther. Patents, 12(3), 419-432, 2002; Leung-Toung,R. et al. Curr. Med. Chem., 9, 979-1002, 2002; Lecaille, F. et al.,Chem. Rev., 102, 4459-4488, 2002; Hernandez, A. A. and Roush, W. R.,Curr. Opin. Chem. Biol., 6, 459-465, 2002). Considering the CAC1 familymembers, particular emphasis has been placed upon the development ofinhibitors of human cathepsins, primarily cathepsin K (osteoporosis),cathepsin S (autoimmune disorders), cathepsin L (metastases), cathepsinB (metastases, arthritis), cathepsin F (antigen processing), cathepsin V(T-cell selection) and dipeptidyl peptidase I (granulocyte serineproteinase activation), through the use of peptide and peptidomimeticnitriles (e.g. see WO-A-03041649, WO-A-03037892, WO-A-03029200,WO-A-02051983, WO-A-02020485, US-A-20020086996, WO-A-01096285,WO-A-0109910, WO-A-0051998, WO-A-0119816, WO-A-9924460, WO-A-0049008,WO-A-0048992, WO-A-0049007, WO-A-0130772, WO-A-0055125, WO-A-0055126,WO-A-0119808, WO-A-0149288, WO-A-0147886), linear and cyclic peptide andpeptidomimetic ketones (e.g. see Veber, D. F. and Thompson, S. K., Curr.Opin. Drug Discovery Dev., 3(4), 362-369, 2000, WO-A-02092563,WO-A-02017924, WO-A-01095911, WO-A-0170232, WO-A-0178734, WO-A-0009653,WO-A-0069855, WO-A-0029408, WO-A-0134153 to WO-A-0134160, WO-A-0029408,WO-A-9964399, WO-A-9805336, WO-A-9850533), ketoheterocycles (e.g. seeWO-A-02080920, WO-A-03042197, WO-A-WO-A-03024924, WO-A-0055144,WO-A-0055124), monobactams (e.g. see WO-A-0059881, WO-A-9948911,WO-A-0109169), α-ketoamides (e.g. see WO-A-03013518), cyanoamides(WO-A-01077073, WO-A-01068645), dihydro pyrimidines (e.g. seeWO-A-02032879) and cyanoaminopyrimidines (e.g. see WO-A-03020278,WO-A-03020721).

The prior art describes potent in vitro inhibitors, but also highlightsthe many difficulties in developing a human therapeutic. For example,WO-A-9850533 and WO-A-0029408 describe compounds that may be referred toas cyclic ketones (e.g. 1′a-f) and are inhibitors of cysteineproteinases with a particular reference towards papain familyproteinases and as a most preferred embodiment, cathepsin K.WO-A-9850533 describes compounds subsequently detailed in the literatureas potent inhibitors of cathepsin K with good oral bioavailability(Witherington, J., ‘Tetrahydrofurans as Selective Cathepsin KInhibitors’, RSC meeting, Burlington House, London, 1999). The compoundsof WO-A-9850533 were reported to bind to cathepsin K through theformation of a reversible covalent bond between the tetrahydrofurancarbonyl and the active site catalytic cysteine residue (Witherington,J., 1999). Additionally, the same cyclic ketone compounds are describedin WO-A-9953039 as part of a wide-ranging description of inhibitors ofcysteine proteinases associated with parasitic diseases, with particularreference to the treatment of malaria by inhibition of falcipain.

Prior Art Cyclic Inhibitors of Cathepsin K

The initial cyclic inhibitors of GSK were based upon potent, selectiveand reversible 3-amido-tetrahydrofuran-4-ones [1′a],3-amidopyrrolidin-4-ones [1′b], 4-amido-tetrahydropyran-3-ones [1′c],4-amidopiperidin-3-ones [1′d] and 4-amidoazepan-3-ones [1′e, 1′f] (shownabove) [see (a) Marquis, R. W. et al, J. Med. Chem. 2001, 44, 725, andreferences cited therein; (b) Marquis, R. W. et al, J. Med. Chem. 2001,44, 1380, and references cited therein; (c) Yamashita, D. S. et al, J.Med. Chem. 2006, 49(5), 1597-1612].

Further studies revealed that cyclic ketones [1′], in particular thefive-membered ring analogues [1′a] and [1′b], suffered fromconfigurational instability due to facile epimerisation at the centresituated α to the ketone [Marquis, R. W. et al, J. Med. Chem. 2001, 44,1380; Fenwick, A. E. et al, J. Bioorg. Med. Chem. Lett. 2001, 11, 199;WO 00/69855]. This precluded the pre-clinical optimisation of inhibitorsof formulae [1′a-d] and led to the development of the configurationallymore stable azepanone series [1′e], providing the cathepsin K inhibitorclinical candidate relacatib [1′f]. However, literature clearly statesthat azepanones are still prone to epimerisation and indeed relacatib[1′f] is reported to exist as a 9:1 thermodynamic mixture of 4-S and 4-Risomers [Yamashita, D. S. et al, J. Med. Chem., 2006, 49(5), 1597-1612].As an alternative to the ring expansion approach, alkylation of theα-carbon removes the ability of cyclic ketones [1′] to undergoα-enolisation and hence leads to configurational stability. However,studies have shown that α-methylation in the 3-amidopyrrolidin-4-one[1′b] system results in a substantial loss in potency versus cathepsin Kfrom K_(i,app)≈0.18 to 50 nM.

The cyclic ketone compounds of WO-A-0069855 are considered to be anadvance on compounds of WO-A-9850533 due to the presence of the□-substituent on the cyclic ketone ring system that provides improvedchiral stability to the α-carbon of the cyclic ketone ring system.However, the compounds of WO-A-0069855 and indeed those of WO-A-9850533describe a requirement for the presence of the potentialhydrogen-bonding motif X—NHCHRCO—NH—Y that is widely observed amongstthe prior art substrate-based inhibitors of CAC1 proteinases.

More recent studies have investigated 5,5-bicyclic systems as inhibitorsof CAC1 proteinases, for example,N-(3-oxo-hexahydrocyclopenta[b]furan-3a-yl)acylamide bicyclic ketones[2′] [(a) Quibell, M.; Ramjee, M. K., WO 02/57246; (b) Watts, J. et al,Bioorg. Med. Chem. 2004, 12, 2903-2925],tetrahydrofuro[3,2-b]pyrrol-3-one based scaffolds [3′] [(a) Quibell, M.WO02/57270; (b) Quibell, M. et al, Bioorg. Med. Chem., 2004, 12,5689-5710], cis-6-oxohexahydro-2-oxa-1,4-diazapentalene andcis-6-oxo-hexahydropyrrolo[3,2-c]pyrazole based scaffolds [4′] [Wang, Y.et al, Bioorg. Med. Chem. Lett., 2005, 15, 1327-1331], andcis-hexahydropyrrolo[3,2-b]pyrrol-3-one based scaffolds [5′] [a)Quibell, M. WO04/07501; (b) Quibell, M. et al, Bioorg. Med. Chem., 2005,13, 609-625].

5,5-bicyclic Inhibitors of CAC1 Cysteinyl Proteinases

Studies have shown that the above-described 5,5-bicyclic systems exhibitpromising potency as inhibitors of a range of therapeutically attractivemammalian and parasitic CAC1 cysteinyl proteinase targets. Moreover, the5,5-bicyclic series are chirally stable due to a marked energeticpreference for a cis-fused rather than a trans-fused geometry. Thischiral stability provides a major advance when compared to monocyclicsystems that often show limited potential for preclinical developmentdue to chiral instability.

PCT applications WO-A-02057270 and WO-A-04007501 describe bicycliccompounds in which the chirality of the α-aminoketone is stabilised (fora review of energetic considerations within fused ring systems see (a)Toromanoff, E. Tetrahedron Report No 96, 36, 2809-2931, 1980; (b) Eliel,E. L. et. al. Stereochemistry of Organic Compounds, Wiley: New York,1-1267, 1994). These compounds do not contain the X—NHCHRCO—NH—Y motifand yet the compounds are highly potent inhibitors across a broad rangeof CAC1 cysteine proteinases. In particular, certain of the compoundsare potent and selective inhibitors of a range of mammalian andparasitic CAC1 proteinases.

More recently, Quibell, M. et al (Bioorg. Med. Chem. 12, 5689-5710,2004) disclosed two potent and selective cathepsin K inhibitors having atetrahydrofuro[3,2-b]pyrrol-3-one core, along with in vitro potency andin vitro selectivity data. Further kinetic parameters such as enzymeassociation (kon) and dissociation (koff) rates were disclosed, as wellas basic physiochemical parameters such as plasma and microsomestability, Caco-2 permeability and LogD (pH_(7.4)) measurements.

The present inventors have now discovered a small genus oftetrahydrofuro[3,2-b]pyrrol-3-ones that exhibit potent in vitroinhibition versus human cathepsin K. Advantageously, the claimedcompounds also display favourable pharmacokinetic properties and ahighly preferred subset exhibit potent osteoclast activity versus humancells.

STATEMENT OF INVENTION

A first aspect of the invention relates to a compound of formula (I), ora pharmaceutically acceptable salt, hydrate, complex or pro-drugthereof,

wherein:X is CH or N;one of R¹ and R² is H, and the other is selected from OR⁶, SR⁶, NR⁶R⁷,N₃, Me, Et, CF₃, SOR⁸ and SO₂R⁸;R³ is selected from tert-butylmethyl, iso-propylmethyl, sec-butyl,tert-butyl, cyclopentyl and cyclohexyl;R⁴ is optionally substituted C₁₋₈ alkyl or optionally substituted C₃₋₈cycloalkyl;R⁶ and R⁷ are each independently selected from H, C₁₋₈-alkyl andC₃₋₈-cycloalkyl, or R⁶ and R⁷ are linked to form a cyclic group togetherwith the nitrogen to which they are attached; andR⁸ is C₁₋₈-alkyl or C₃₋₈-cycloalkyl.

As mentioned above, compounds of formula (I) exhibit surprisingly highefficacies for human cathepsin K. Indeed, all of the compounds preparedto date exhibit potent in vitro inhibition versus human cathepsin K withKi<50 nM. Furthermore, preferred compounds of formula (I) also exhibitdesirable pharmacokinetic properties and potent cross species osteoclastactivity, contrary to many cathepsin K inhibitors known in the art. Inaddition, preferred compounds of formula (I) also exhibit surprisinglygood stability in plasma and microsome assays.

A second aspect of the invention relates to a pharmaceutical orveterinary composition comprising a compound of formula (I) and apharmaceutically acceptable or veterinarily acceptable diluent,excipient and/or carrier.

A third aspect of the invention relates to a process for preparing apharmaceutical or veterinary composition as defined above, said processcomprising admixing a compound of the invention with a pharmaceuticallyacceptable or veterinarily acceptable diluent, excipient and/or carrier.

A fourth aspect of the invention relates to compounds of formula (I) foruse in medicine.

A fifth aspect of the invention relates to the use of a compound offormula (I) in the preparation of a medicament for treating a diseaseselected from osteoporosis, Paget's disease, Chagas's disease, malaria,gingival diseases, hypercalaemia, metabolic bone disease, diseasesinvolving matrix or cartilage degradation, and bone cancer disorderssuch as bone metastases and associated pain.

A sixth aspect of the invention relates to a method of inhibiting acysteine proteinase in a cell, said method comprising contacting saidcell with a compound of formula (I).

A seventh aspect of the invention relates to method of inhibiting acysteine proteinase in a subject, said method comprising administeringto the subject a pharmacologically effective amount of a compound offormula (I).

An eighth aspect of the invention relates to a method of treating adisease selected from osteoporosis, Paget's disease, Chagas's disease,malaria, gingival diseases, hypercalaemia, metabolic bone disease,diseases involving matrix or cartilage degradation, and bone cancerdisorders such as bone metastases and associated pain, in a subject,said method comprising administering to the subject a pharmacologicallyeffective amount of a compound of formula (I).

A ninth aspect of the invention relates to the use of a compoundaccording to the invention in an assay for identifying further candidatecompounds capable of inhibiting one or more cysteine proteinases.

A tenth aspect of the invention relates to the use of a compound offormula (I) in the validation of a known or putative cysteine proteinaseas a therapeutic target.

An eleventh aspect of the invention relates to a process of preparing acompound of formula (I).

DETAILED DESCRIPTION

The term ‘alkyl’ as applied herein includes stable straight and branchedchain aliphatic carbon chains which may be optionally substituted.Preferred examples include methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, t-butyl, pentyl, isopentyl, hexyl, heptyl and any simpleisomers thereof. Suitable substituents include, for example, one or moreC₁₋₆ alkoxy, OH, COOH, COOMe, NH₂, NMe₂, NHMe, NO₂, CN, CF₃ and/or halogroups. Additionally, where the alkyl group contains two or morecontiguous carbon atoms, an alkene group (—CH═CH—) or alkyne group(—C≡C—) may be present. Furthermore, the alkyl group may optionallycontain one or more heteroatoms for example, to give ethers, thioethers,sulphones, sulphonamides, substituted amines, amidines, guanidines,carboxylic acids, carboxamides. If the heteroatom is located at a chainterminus then it is appropriately substituted with one or two hydrogenatoms. For example, the group CH₃—CH₂—O—CH₂—CH₂— is defined within‘alkyl’ as a C₄ alkyl that contains a centrally positioned heteroatomwhereas the group CH₃—CH₂—CH₂—CH₂— is defined within ‘alkyl’ as anunsubstituted C₄ alkyl.

Preferably, the alkyl group is a C₁₋₈ alkyl group, more preferably aC₁₋₆ group, even more preferably a C₁₋₄ alkyl group.

As used herein, the term “cycloalkyl” refers to a cyclic alkyl group(i.e. a carbocyclic ring) which may be substituted (mono- or poly-) orunsubstituted. Suitable substituents include, for example, one or moreC₁₋₆ alkyl, C₁₋₆ alkoxy, OH, COOH, COOMe, NH₂, NMe₂, NHMe, NO₂, CN, CF₃and/or halo groups. Preferably, the cycloalkyl group is a C₃₋₈cycloalkyl group, more preferably a C₃₋₆-cycloalkyl, even morepreferably a C₃₋₄ cycloalkyl group. Examples include cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl and the like. In addition, thecarbocyclic ring itself may optionally contain one or more heteroatoms,for example, to give a heterocycloalkyl group such as tetrahydrofuran,pyrrolidine, piperidine, piperazine or morpholine.

‘Halogen’ or ‘halo’ as applied herein encompasses F, Cl, Br, I.

‘Heteroatom’ as applied herein encompasses O, S, P and N, morepreferably, O, S and N.

The present invention includes all salts, hydrates, solvates, complexesand prodrugs of the compounds of this invention. The term “compound” isintended to include all such salts, hydrates, solvates, complexes andprodrugs, unless the context requires otherwise.

In particular, the skilled person will appreciate that the ketone groupof the bicycle core of compounds of formula (I) may exist in alternativeforms such as the hydrate (as shown below), and the invention extends toall such alternative forms.

Abbreviations and symbols commonly used in the peptide and chemical artsare used herein to describe compounds of the present invention,following the general guidelines presented by the IUPAC-IUB JointCommission on Biochemical Nomenclature as described in Eur. J. Biochem.,158, 9-, 1984. Compounds of formula (I) and the intermediates andstarting materials used in their preparation are named in accordancewith the IUPAC rules of nomenclature in which the characteristic groupshave decreasing priority for citation as the principle group.

In one preferred embodiment, the compound of the invention is of formulaIa

wherein X, R¹, R², R³ and R⁴ are as defined above.

In more preferred embodiment, R³ is cyclohexyl such that the centralmoiety is the amino acid (S)-cyclohexylglycine.

In one highly preferred embodiment, R³ is cyclopentyl such that thecentral moiety is the amino acid (S)-cyclopentylglycine.

In one preferred embodiment, R³ is iso-propylmethyl such that thecentral moiety is the amino acid (S)-leucine.

In one preferred embodiment, R³ is tert-butyl such that the centralmoiety is the amino acid (S)-tert-butylglycine.

In another preferred embodiment, R³ is sec-butyl of S-configuration suchthat the central moiety is the amino acid (2S,3S)-isoleucine.

In another preferred embodiment, R³ is tert-butylmethyl such that thecentral moiety is the amino acid (S)-tert-butylalanine.

In one highly preferred embodiment, R³ is tert-butylmethyl such that thecentral moiety is the amino acid (S)-tert-butylalanine.

In one preferred embodiment, X is CH.

In another preferred embodiment, X is N.

In one preferred embodiment, R⁴ is an unsubstituted C₃₋₆ cycloalkylgroup.

In one preferred embodiment, R⁴ is a C₁₋₆ alkyl group optionallysubstituted by one or more C₁₋₆ alkoxy groups.

Even more preferably, R⁴ is selected from methyl, ethyl, n-propyl,isopropyl, cyclopropyl, n-butyl, s-butyl, i-butyl, tert-butyl,cyclobutyl and 2-methoxyethyl.

Yet even more preferably, R⁴ is selected from methyl, ethyl, n-propyl,isopropyl, cyclopropyl, cyclobutyl and 2-methoxyethyl.

In one preferred embodiment, R³ is selected from tert-butylmethyl,sec-butyl, tert-butyl, cyclopentyl and cyclohexyl.

In another preferred embodiment, R³ is cyclopentyl or cyclohexyl.

In one preferred embodiment, R⁶ and R⁷ are each independently H,C₁₋₄-alkyl or C₃₋₆-cycloalkyl.

In more preferred embodiment, R⁶ and R⁷ are each independently selectedfrom H, methyl, ethyl, isopropyl, n-propyl, iso-butyl, sec-butyl,tert-butyl, cyclopropyl and cyclobutyl.

In another preferred embodiment, R⁶ and R⁷ are linked to form analkylene group,

wherein p is 1, 2, 3 or 4.

In one preferred embodiment, one of R¹ and R² is H, and the other isselected from Me, Et, CF₃, OH, OMe, OEt, O^(n)Pr, O^(i)Pr,O-cyclopropyl, O-cyclobutyl, SH, SMe, SEt, S^(n)Pr, S^(i)Pr,S-cyclopropyl, S-cyclobutyl, NH₂, NHMe, NHEt, NH^(n)Pr, NH^(i)Pr,NH-cyclopropyl, NH-cyclobutyl, NMe₂, N₃, SOMe, SOEt, SO^(n)Pr, SO^(i)Pr,SO-cyclopropyl, SO-cyclobutyl, SO₂Me, SO₂Et, SO₂ ^(n)Pr, SO₂ ^(i)Pr,SO₂-cyclopropyl, SO₂-cyclobutyl and

More preferably, one of R¹ and R² is H, and the other is selected fromOH, OMe, OEt, O^(n)Pr, O^(i)Pr, O-cyclopropyl, O-cyclobutyl, SH, SMe,SEt, S^(n)Pr, S^(n)Pr, S-cyclopropyl, S-cyclobutyl, NH₂, NHMe, NHEt,NH^(n)Pr, NH^(i)Pr, NH-cyclopropyl, NH-cyclobutyl, NMe₂, N₃, SOMe, SOEt,SO^(n)Pr, SO^(i)Pr, SO-cyclopropyl, SO-cyclobutyl, SO₂Me, SO₂Et, SO₂^(n)Pr, SO₂ ^(i)Pr, SO₂-cyclopropyl, SO₂-cyclobutyl and

Even more preferably, one of R¹ and R² is H, and the other is selectedfrom OH, OMe, OEt, O^(n)Pr, O^(i)Pr, O-cyclopropyl, O-cyclobutyl, SH,SMe, SEt, S^(n)Pr, S^(i)Pr, S-cyclopropyl, S-cyclobutyl, NH₂, NHMe,NHEt, NH^(n)Pr, NH^(i)Pr, NMe₂ and N₃.

In one highly preferred embodiment,

R¹ is OH, OMe, OEt, SMe, NH₂, NHMe, NMe₂ or N₃ and R² is H; or

R² is OH, OMe, OEt, SMe, NH₂, NHMe, NMe₂ or N₃ and R¹ is H.

In an even more preferred embodiment,

R¹ is OH, OMe, OEt, NH₂, NHMe, SMe or N₃, and R² is H; or

R² is OH, OMe, NH₂ or N₃, and R¹ is H.

In one highly preferred embodiment, the compound of the invention isselected from the following:

-   N—((S)-1-((3aS,6S,6aS)-6-hydroxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)-4-(4-propylpiperazin-1-yl)benzamide-   N—((S)-1-((3aS,6S,6aS)-6-hydroxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)-4-(4-isopropylpiperazin-1-yl)benzamide-   4-(4-cyclopropylpiperazin-1-yl)-N—((S)-1-((3aS,6S,6aS)-6-hydroxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)benzamide-   4-(4-cyclobutylpiperazin-1-yl)-N—((S)-1-((3aS,6S,6aS)-6-hydroxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)benzamide-   4-(1-cyclopropylpiperidin-4-yl)-N—((S)-1-((3aS,6S,6aS)-6-hydroxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)benzamide-   4-(1-cyclobutylpiperidin-4-yl)-N—((S)-1-((3aS,6S,6aS)-6-hydroxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)benzamide-   N—((S)-1-((3aS,6S,6aS)-6-hydroxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)-4-(4-propylpiperazin-1-yl)benzamide-   N—((S)-1-((3aS,6S,6aS)-6-hydroxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)-4-(4-isopropylpiperazin-1-yl)benzamide-   4-(4-cyclopropylpiperazin-1-yl)-N—((S)-1-((3aS,6S,6aS)-6-hydroxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)benzamide-   4-(4-cyclobutylpiperazin-1-yl)-N—((S)-1-((3aS,6S,6aS)-6-hydroxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)benzamide-   4-(1-cyclopropylpiperidin-4-yl)-N—((S)-1-((3aS,6S,6aS)-6-hydroxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)benzamide-   4-(1-cyclobutylpiperidin-4-yl)-N—((S)-1-((3aS,6S,6aS)-6-hydroxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)benzamide-   4-(4-ethylpiperazin-1-yl)-N-((2S,3S)-1-((3aS,6S,6aS)-6-hydroxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)benzamide-   N-((2S,3S)-1-((3aS,6S,6aS)-6-hydroxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)-4-(4-propylpiperazin-1-yl)benzamide-   N-((2S,3S)-1-((3aS,6S,6aS)-6-hydroxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)-4-(4-isopropylpiperazin-1-yl)benzamide-   4-(4-cyclopropylpiperazin-1-yl)-N-((2S,3S)-1-((3aS,6S,6aS)-6-hydroxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)benzamide-   4-(4-cyclobutylpiperazin-1-yl)-N-((2S,3S)-1-((3aS,6S,6aS)-6-hydroxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)benzamide-   4-(1-cyclopropylpiperidin-4-yl)-N-((2S,3S)-1-((3aS,6S,6aS)-6-hydroxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)benzamide-   4-(1-cyclobutylpiperidin-4-yl)-N-((2S,3S)-1-((3aS,6S,6aS)-6-hydroxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)benzamide-   4-(4-ethylpiperazin-1-yl)-N—((S)-1-((3aS,6S,6aS)-6-hydroxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxobutan-2-yl)benzamide-   N—((S)-1-((3aS,6S,6    aS)-6-hydroxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxobutan-2-yl)-4-(4-propylpiperazin-1-yl)benzamide-   N—((S)-1-((3aS,6S,6aS)-6-hydroxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxobutan-2-yl)-4-(4-isopropylpiperazin-1-yl)benzamide-   4-(4-cyclopropylpiperazin-1-yl)-N—((S)-1-((3aS,6S,6aS)-6-hydroxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxobutan-2-yl)benzamide-   4-(4-cyclobutylpiperazin-1-yl)-N—((S)-1-((3aS,6S,6aS)-6-hydroxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxobutan-2-yl)benzamide-   4-(1-cyclopropylpiperidin-4-yl)-N—((S)-1-((3aS,6S,6aS)-6-hydroxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxobutan-2-yl)benzamide-   4-(1-cyclobutylpiperidin-4-yl)-N—((S)-1-((3aS,6S,6aS)-6-hydroxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxobutan-2-yl)benzamide-   N—((S)-1-cyclopentyl-2-((3aS,6S,6aS)-6-hydroxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-methylpiperazin-1-yl)benzamide-   N—((S)-1-cyclopentyl-2-((3aS,6S,6aS)-6-hydroxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-ethylpiperazin-1-yl)benzamide-   N—((S)-1-cyclopentyl-2-((3aS,6S,6aS)-6-hydroxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-propylpiperazin-1-yl)benzamide-   N—((S)-1-cyclopentyl-2-((3aS,6S,6aS)-6-hydroxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-isopropylpiperazin-1-yl)benzamide-   N—((S)-1-cyclopentyl-2-((3aS,6S,6aS)-6-hydroxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-(2-methoxyethyl)piperazin-1-yl)benzamide-   N—((S)-1-cyclopentyl-2-((3aS,6S,6aS)-6-hydroxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-cyclopropylpiperazin-1-yl)benzamide-   4-(4-cyclobutylpiperazin-1-yl)-N—((S)-1-cyclopentyl-2-((3aS,6S,6aS)-6-hydroxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)benzamide-   N—((S)-1-cyclopentyl-2-((3aS,6S,6aS)-6-hydroxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(1-propylpiperidin-4-yl)benzamide-   N—((S)-1-cyclopentyl-2-((3aS,6S,6aS)-6-hydroxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(1-isopropylpiperidin-4-yl)benzamide-   N—((S)-1-cyclopentyl-2-((3aS,6S,6aS)-6-hydroxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(1-cyclopropylpiperidin-4-yl)benzamide-   4-(1-cyclobutylpiperidin-4-yl)-N—((S)-1-cyclopentyl-2-((3aS,6S,6aS)-6-hydroxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)benzamide-   N—((S)-1-cyclohexyl-2-((3aS,6S,6aS)-6-hydroxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-methylpiperazin-1-yl)benzamide-   N—((S)-1-cyclohexyl-2-((3aS,6S,6aS)-6-hydroxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-ethylpiperazin-1-yl)benzamide-   N—((S)-1-cyclohexyl-2-((3aS,6S,6aS)-6-hydroxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-propylpiperazin-1-yl)benzamide-   N—((S)-1-cyclohexyl-2-((3aS,6S,6aS)-6-hydroxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-isopropylpiperazin-1-yl)benzamide-   N—((S)-1-cyclohexyl-2-((3aS,6S,6aS)-6-hydroxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-(2-methoxyethyl)piperazin-1-yl)benzamide-   N—((S)-1-cyclohexyl-2-((3aS,6S,6aS)-6-hydroxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-cyclopropylpiperazin-1-yl)benzamide-   4-(4-cyclobutylpiperazin-1-yl)-N—((S)-1-cyclohexyl-2-((3aS,6S,6aS)-6-hydroxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)benzamide-   N—((S)-1-cyclohexyl-2-((3aS,6S,6aS)-6-hydroxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(1-propylpiperidin-4-yl)benzamide-   N—((S)-1-cyclohexyl-2-((3aS,6S,6aS)-6-hydroxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(1-isopropylpiperidin-4-yl)benzamide-   N—((S)-1-cyclohexyl-2-((3aS,6S,6aS)-6-hydroxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(1-cyclopropylpiperidin-4-yl)benzamide-   4-(1-cyclobutylpiperidin-4-yl)-N—((S)-1-cyclohexyl-2-((3aS,6S,6aS)-6-hydroxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)benzamide-   N—((S)-1-((3aS,6S,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)-4-(4-methylpiperazin-1-yl)benzamide-   4-(4-ethylpiperazin-1-yl)-N—((S)-1-((3aS,6S,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)benzamide-   N—((S)-1-((3aS,6S,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)-4-(4-propylpiperazin-1-yl)benzamide-   4-(4-isopropylpiperazin-1-yl)-N—((S)-1-((3aS,6S,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)benzamide-   N—((S)-1-((3aS,6S,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)-4-(4-(2-methoxyethyl)piperazin-1-yl)benzamide-   4-(4-cyclopropylpiperazin-1-yl)-N—((S)-1-((3aS,6S,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)benzamide-   4-(4-cyclobutylpiperazin-1-yl)-N—((S)-1-((3aS,6S,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)benzamide-   N—((S)-1-((3aS,6S,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)-4-(1-propylpiperidin-4-yl)benzamide-   4-(1-isopropylpiperidin-4-yl)-N—((S)-1-((3aS,6S,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)benzamide-   N—((S)-1-((3aS,6S,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)-4-(1-(2-methoxyethyl)piperidin-4-yl)benzamide-   4-(1-cyclopropylpiperidin-4-yl)-N—((S)-1-((3aS,6S,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)benzamide-   4-(1-cyclobutylpiperidin-4-yl)-N—((S)-1-((3aS,6S,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)benzamide-   N—((S)-1-((3aS,6S,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)-4-(4-methylpiperazin-1-yl)benzamide-   4-(4-ethylpiperazin-1-yl)-N—((S)-1-((3aS,6S,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)benzamide-   N—((S)-1-((3aS,6S,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)-4-(4-propylpiperazin-1-yl)benzamide-   4-(4-isopropylpiperazin-1-yl)-N—((S)-1-((3aS,6S,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)benzamide-   N—((S)-1-((3aS,6S,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)-4-(4-(2-methoxyethyl)piperazin-1-yl)benzamide-   4-(4-cyclopropylpiperazin-1-yl)-N—((S)-1-((3aS,6S,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)benzamide-   4-(4-cyclobutylpiperazin-1-yl)-N—((S)-1-((3aS,6S,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)benzamide-   N—((S)-1-((3aS,6S,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)-4-(1-propylpiperidin-4-yl)benzamide-   4-(1-cyclopropylpiperidin-4-yl)-N—((S)-1-((3aS,6S,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)benzamide-   4-(1-cyclobutylpiperidin-4-yl)-N—((S)-1-((3aS,6S,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)benzamide-   N-((2S,3S)-1-((3aS,6S,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)-4-(4-methylpiperazin-1-yl)benzamide-   4-(4-ethylpiperazin-1-yl)-N-((2S,3S)-1-((3aS,6S,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)benzamide-   N-((2S,3S)-1-((3aS,6S,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)-4-(4-propylpiperazin-1-yl)benzamide-   4-(4-isopropylpiperazin-1-yl)-N-((2S,3S)-1-((3aS,6S,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)benzamide-   N-((2S,3S)-1-((3aS,6S,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)-4-(1-(2-methoxyethyl)piperazin-4-yl)benzamide-   4-(4-cyclopropylpiperazin-1-yl)-N-((2S,3S)-1-((3aS,6S,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)benzamide-   4-(4-cyclobutylpiperazin-1-yl)-N-((2S,3S)-1-((3aS,6S,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)benzamide-   N-((2S,3S)-1-((3aS,6S,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)-4-(1-methylpiperidin-4-yl)benzamide-   4-(1-ethylpiperidin-4-yl)-N-((2S,3S)-1-((3aS,6S,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)benzamide-   N-((2S,3S)-1-((3aS,6S,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)-4-(1-propylpiperidin-4-yl)benzamide-   4-(1-isopropylpiperidin-4-yl)-N-((2S,3S)-1-((3aS,6S,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)benzamide-   N-((2S,3S)-1-((3aS,6S,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)-4-(1-(2-methoxyethyl)piperidin-4-yl)benzamide-   4-(1-cyclopropylpiperidin-4-yl)-N-((2S,3S)-1-((3aS,6S,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)benzamide-   4-(1-cyclobutylpiperidin-4-yl)-N-((2S,3S)-1-((3aS,6S,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)benzamide-   N—((S)-1-((3aS,6S,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxobutan-2-yl)-4-(4-methylpiperazin-1-yl)benzamide-   4-(4-ethylpiperazin-1-yl)-N—((S)-1-((3aS,6S,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxobutan-2-yl)benzamide-   N—((S)-1-((3aS,6S,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxobutan-2-yl)-4-(4-propylpiperazin-1-yl)benzamide-   4-(4-isopropylpiperazin-1-yl)-N—((S)-1-((3aS,6S,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxobutan-2-yl)benzamide-   N—((S)-1-((3aS,6S,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxobutan-2-yl)-4-(4-(2-methoxyethyl)piperazin-1-yl)benzamide-   4-(4-cyclopropylpiperazin-1-yl)-N—((S)-1-((3aS,6S,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxobutan-2-yl)benzamide-   4-(4-cyclobutylpiperazin-1-yl)-N—((S)-1-((3aS,6S,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxobutan-2-yl)benzamide-   N—((S)-1-((3aS,6S,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxobutan-2-yl)-4-(1-propylpiperidin-4-yl)benzamide-   4-(1-cyclopropylpiperidin-4-yl)-N—((S)-1-((3aS,6S,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxobutan-2-yl)benzamide-   4-(1-cyclobutylpiperidin-4-yl)-N—((S)-1-((3aS,6S,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxobutan-2-yl)benzamide-   N—((S)-1-cyclopentyl-2-((3aS,6S,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-methylpiperazin-1-yl)benzamide-   N—((S)-1-cyclopentyl-2-((3aS,6S,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-ethylpiperazin-1-yl)benzamide-   N—((S)-1-cyclopentyl-2-((3aS,6S,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-propylpiperazin-1-yl)benzamide-   N—((S)-1-cyclopentyl-2-((3aS,6S,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-isopropylpiperazin-1-yl)benzamide-   N—((S)-1-cyclopentyl-2-((3aS,6S,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-(2-methoxyethyl)piperazin-1-yl)benzamide-   N—((S)-1-cyclopentyl-2-((3aS,6S,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-cyclopropylpiperazin-1-yl)benzamide-   4-(4-cyclobutylpiperazin-1-yl)-N—((S)-1-cyclopentyl-2-((3aS,6S,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)benzamide-   N—((S)-1-cyclopentyl-2-((3aS,6S,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(1-propylpiperidin-4-yl)benzamide-   N—((S)-1-cyclopentyl-2-((3aS,6S,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(1-cyclopropylpiperidin-4-yl)benzamide-   4-(1-cyclobutylpiperidin-4-yl)-N—((S)-1-cyclopentyl-2-((3aS,6S,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)benzamide-   N—((S)-1-cyclohexyl-2-((3aS,6S,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-methylpiperazin-1-yl)benzamide-   N—((S)-1-cyclohexyl-2-((3aS,6S,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-ethylpiperazin-1-yl)benzamide-   N—((S)-1-cyclohexyl-2-((3aS,6S,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-propylpiperazin-1-yl)benzamide-   N—((S)-1-cyclohexyl-2-((3aS,6S,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-isopropylpiperazin-1-yl)benzamide-   N—((S)-1-cyclohexyl-2-((3aS,6S,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-(2-methoxyethyl)piperazin-1-yl)benzamide-   N—((S)-1-cyclohexyl-2-((3aS,6S,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-cyclopropylpiperazin-1-yl)benzamide-   4-(4-cyclobutylpiperazin-1-yl)-N—((S)-1-cyclohexyl-2-((3aS,6S,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)benzamide-   N—((S)-1-cyclohexyl-2-((3aS,6S,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(1-methylpiperidin-4-yl)benzamide-   N—((S)-1-cyclohexyl-2-((3aS,6S,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(1-ethylpiperidin-4-yl)benzamide-   N—((S)-1-cyclohexyl-2-((3aS,6S,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(1-propylpiperidin-4-yl)benzamide-   N—((S)-1-cyclohexyl-2-((3aS,6S,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(1-isopropylpiperidin-4-yl)benzamide-   N—((S)-1-cyclohexyl-2-((3aS,6S,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(1-(2-methoxyethyl)piperidin-4-yl)benzamide-   N—((S)-1-cyclohexyl-2-((3aS,6S,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(1-cyclopropylpiperidin-4-yl)benzamide-   4-(1-cyclobutylpiperidin-4-yl)-N—((S)-1-cyclohexyl-2-((3aS,6S,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)benzamide-   N—((S)-1-((3aS,6S,6aS)-6-ethoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)-4-(4-methylpiperazin-1-yl)benzamide-   N—((S)-1-((3aS,6S,6aS)-6-ethoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)-4-(4-ethylpiperazin-1-yl)benzamide-   N—((S)-1-((3aS,6S,6aS)-6-ethoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)-4-(4-propylpiperazin-1-yl)benzamide-   N—((S)-1-((3aS,6S,6aS)-6-ethoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)-4-(4-isopropylpiperazin-1-yl)benzamide-   N—((S)-1-((3aS,6S,6aS)-6-ethoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)-4-(4-(2-methoxyethyl)piperazin-1-yl)benzamide-   4-(4-cyclopropylpiperazin-1-yl)-N—((S)-1-((3aS,6S,6aS)-6-ethoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)benzamide-   4-(4-cyclobutylpiperazin-1-yl)-N—((S)-1-((3aS,6S,6aS)-6-ethoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)benzamide-   N—((S)-1-((3aS,6S,6aS)-6-ethoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)-4-(1-propylpiperidin-4-yl)benzamide-   N—((S)-1-((3aS,6S,6aS)-6-ethoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)-4-(1-isopropylpiperidin-4-yl)benzamide-   N—((S)-1-((3aS,6S,6aS)-6-ethoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)-4-(1-(2-methoxyethyl)piperidin-4-yl)benzamide-   4-(1-cyclopropylpiperidin-4-yl)-N—((S)-1-((3aS,6S,6aS)-6-ethoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)benzamide-   4-(1-cyclobutylpiperidin-4-yl)-N—((S)-1-((3aS,6S,6aS)-6-ethoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)benzamide-   N—((S)-1-((3aS,6S,6aS)-6-ethoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)-4-(4-methylpiperazin-1-yl)benzamide-   N—((S)-1-((3aS,6S,6aS)-6-ethoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)-4-(4-ethylpiperazin-1-yl)benzamide-   N—((S)-1-((3aS,6S,6aS)-6-ethoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)-4-(4-propylpiperazin-1-yl)benzamide-   N—((S)-1-((3aS,6S,6aS)-6-ethoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)-4-(4-isopropylpiperazin-1-yl)benzamide-   N—((S)-1-((3aS,6S,6aS)-6-ethoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)-4-(4-(2-methoxyethyl)piperazin-1-yl)benzamide-   4-(4-cyclopropylpiperazin-1-yl)-N—((S)-1-((3aS,6S,6aS)-6-ethoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)benzamide-   4-(4-cyclobutylpiperazin-1-yl)-N—((S)-1-((3aS,6S,6aS)-6-ethoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)benzamide-   N—((S)-1-((3aS,6S,6aS)-6-ethoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)-4-(1-propylpiperidin-4-yl)benzamide-   4-(1-cyclopropylpiperidin-4-yl)-N—((S)-1-((3aS,6S,6aS)-6-ethoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)benzamide-   4-(1-cyclobutylpiperidin-4-yl)-N—((S)-1-((3aS,6S,6aS)-6-ethoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)benzamide-   N-((2S,3S)-1-((3aS,6S,6aS)-6-ethoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)-4-(4-methylpiperazin-1-yl)benzamide-   N-((2S,3S)-1-((3aS,6S,6aS)-6-ethoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)-4-(4-ethylpiperazin-1-yl)benzamide-   N-((2S,3S)-1-((3aS,6S,6aS)-6-ethoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)-4-(4-propylpiperazin-1-yl)benzamide-   N-((2S,3S)-1-((3aS,6S,6aS)-6-ethoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)-4-(4-isopropylpiperazin-1-yl)benzamide-   N-((2S,3S)-1-((3aS,6S,6aS)-6-ethoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)-4-(4-(2-methoxyethyl)piperazin-1-yl)benzamide-   4-(4-cyclopropylpiperazin-1-yl)-N-((2S,3S)-1-((3aS,6S,6aS)-6-ethoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)benzamide-   4-(4-cyclobutylpiperazin-1-yl)-N-((2S,3S)-1-((3aS,6S,6aS)-6-ethoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)benzamide-   N-((2S,3S)-1-((3aS,6S,6aS)-6-ethoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)-4-(1-methylpiperidin-4-yl)benzamide-   N-((2S,3S)-1-((3aS,6S,6aS)-6-ethoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)-4-(1-ethylpiperidin-4-yl)benzamide-   N-((2S,3S)-1-((3aS,6S,6aS)-6-ethoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)-4-(1-propylpiperidin-4-yl)benzamide-   N-((2S,3S)-1-((3aS,6S,6aS)-6-ethoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)-4-(1-isopropylpiperidin-4-yl)benzamide-   N-((2S,3S)-1-((3aS,6S,6aS)-6-ethoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)-4-(1-(2-methoxyethyl)piperidin-4-yl)benzamide-   4-(1-cyclopropylpiperidin-4-yl)-N-((2S,3S)-1-((3aS,6S,6aS)-6-ethoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)benzamide-   4-(1-cyclobutylpiperidin-4-yl)-N-((2S,3S)-1-((3aS,6S,6aS)-6-ethoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)benzamide-   N—((S)-1-((3aS,6S,6aS)-6-ethoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxobutan-2-yl)-4-(4-methylpiperazin-1-yl)benzamide-   N—((S)-1-((3aS,6S,6aS)-6-ethoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxobutan-2-yl)-4-(4-ethylpiperazin-1-yl)benzamide-   N—((S)-1-((3aS,6S,6aS)-6-ethoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxobutan-2-yl)-4-(4-propylpiperazin-1-yl)benzamide-   N—((S)-1-((3aS,6S,6aS)-6-ethoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxobutan-2-yl)-4-(4-isopropylpiperazin-1-yl)benzamide-   N—((S)-1-((3aS,6S,6aS)-6-ethoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxobutan-2-yl)-4-(4-(2-methoxyethyl)piperazin-1-yl)benzamide-   4-(4-cyclopropylpiperazin-1-yl)-N—((S)-1-((3aS,6S,6aS)-6-ethoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxobutan-2-yl)benzamide-   4-(4-cyclobutylpiperazin-1-yl)-N—((S)-1-((3aS,6S,6aS)-6-ethoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxobutan-2-yl)benzamide-   N—((S)-1-((3aS,6S,6aS)-6-ethoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxobutan-2-yl)-4-(1-propylpiperidin-4-yl)benzamide-   4-(1-cyclopropylpiperidin-4-yl)-N—((S)-1-((3aS,6S,6aS)-6-ethoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxobutan-2-yl)benzamide-   4-(1-cyclobutylpiperidin-4-yl)-N—((S)-1-((3aS,6S,6aS)-6-ethoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxobutan-2-yl)benzamide-   N—((S)-1-cyclopentyl-2-((3aS,6S,6aS)-6-ethoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-methylpiperazin-1-yl)benzamide-   N—((S)-1-cyclopentyl-2-((3aS,6S,6aS)-6-ethoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-ethylpiperazin-1-yl)benzamide-   N—((S)-1-cyclopentyl-2-((3aS,6S,6aS)-6-ethoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-propylpiperazin-1-yl)benzamide-   N—((S)-1-cyclopentyl-2-((3aS,6S,6aS)-6-ethoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-isopropylpiperazin-1-yl)benzamide-   N—((S)-1-cyclopentyl-2-((3aS,6S,6aS)-6-ethoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-(2-methoxyethyl)piperazin-1-yl)benzamide-   N—((S)-1-cyclopentyl-2-((3aS,6S,6aS)-6-ethoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-cyclopropylpiperazin-1-yl)benzamide-   4-(4-cyclobutylpiperazin-1-yl)-N—((S)-1-cyclopentyl-2-((3aS,6S,6aS)-6-ethoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)benzamide-   N—((S)-1-cyclopentyl-2-((3aS,6S,6aS)-6-ethoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(1-methylpiperidin-4-yl)benzamide-   N—((S)-1-cyclopentyl-2-((3aS,6S,6aS)-6-ethoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(1-ethylpiperidin-4-yl)benzamide-   N—((S)-1-cyclopentyl-2-((3aS,6S,6aS)-6-ethoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(1-propylpiperidin-4-yl)benzamide-   N—((S)-1-cyclopentyl-2-((3aS,6S,6aS)-6-ethoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(1-isopropylpiperidin-4-yl)benzamide-   N—((S)-1-cyclopentyl-2-((3aS,6S,6aS)-6-ethoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(1-(2-methoxyethyl)piperidin-4-yl)benzamide-   N—((S)-1-cyclopentyl-2-((3aS,6S,6aS)-6-ethoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(1-cyclopropylpiperidin-4-yl)benzamide-   4-(1-cyclobutylpiperidin-4-yl)-N—((S)-1-cyclopentyl-2-((3aS,6S,6aS)-6-ethoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)benzamide-   N—((S)-1-cyclohexyl-2-((3aS,6S,6aS)-6-ethoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-methylpiperazin-1-yl)benzamide-   N—((S)-1-cyclohexyl-2-((3aS,6S,6aS)-6-ethoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-ethylpiperazin-1-yl)benzamide-   N—((S)-1-cyclohexyl-2-((3aS,6S,6aS)-6-ethoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-propylpiperazin-1-yl)benzamide-   N—((S)-1-cyclohexyl-2-((3aS,6S,6aS)-6-ethoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-isopropylpiperazin-1-yl)benzamide-   N—((S)-1-cyclohexyl-2-((3aS,6S,6aS)-6-ethoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-(2-methoxyethyl)piperazin-1-yl)benzamide-   N—((S)-1-cyclohexyl-2-((3aS,6S,6aS)-6-ethoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-cyclopropylpiperazin-1-yl)benzamide-   4-(4-cyclobutylpiperazin-1-yl)-N—((S)-1-cyclohexyl-2-((3aS,6S,6aS)-6-ethoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)benzamide-   N—((S)-1-cyclohexyl-2-((3aS,6S,6aS)-6-ethoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(1-methylpiperidin-4-yl)benzamide-   N—((S)-1-cyclohexyl-2-((3aS,6S,6aS)-6-ethoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(1-ethylpiperidin-4-yl)benzamide-   N—((S)-1-cyclohexyl-2-((3aS,6S,6aS)-6-ethoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(1-propylpiperidin-4-yl)benzamide-   N—((S)-1-cyclohexyl-2-((3aS,6S,6aS)-6-ethoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(1-isopropylpiperidin-4-yl)benzamide-   N—((S)-1-cyclohexyl-2-((3aS,6S,6aS)-6-ethoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(1-(2-methoxyethyl)piperidin-4-yl)benzamide-   N—((S)-1-cyclohexyl-2-((3aS,6S,6aS)-6-ethoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(1-cyclopropylpiperidin-4-yl)benzamide-   4-(1-cyclobutylpiperidin-4-yl)-N—((S)-1-cyclohexyl-2-((3aS,6S,6aS)-6-ethoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)benzamide-   N—((S)-1-((3aS,6S,6aR)-6-amino-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)-4-(1-propylpiperazin-1-yl)benzamide-   N—((S)-1-((3aS,6S,6aR)-6-amino-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)-4-(1-cyclopropylpiperazin-1-yl)benzamide-   N—((S)-1-((3aS,6S,6aR)-6-amino-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)-4-(1-cyclobutylpiperazin-1-yl)benzamide-   N-((2S,3S)-1-((3aS,6S,6aR)-6-amino-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)-4-(4-ethylpiperazin-1-yl)benzamide-   N-((2S,3S)-1-((3aS,6S,6aR)-6-amino-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)-4-(4-propylpiperazin-1-yl)benzamide-   N-((2S,3S)-1-((3aS,6S,6aR)-6-amino-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)-4-(4-isopropylpiperazin-1-yl)benzamide-   N-((2S,3S)-1-((3aS,6S,6aR)-6-amino-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)-4-(4-cyclopropylpiperazin-1-yl)benzamide-   N-((2S,3S)-1-((3aS,6S,6aR)-6-amino-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)-4-(4-cyclobutylpiperazin-1-yl)benzamide-   N—((S)-1-((3aS,6S,6aR)-6-amino-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxobutan-2-yl)-4-(4-propylpiperazin-1-yl)benzamide-   N—((S)-1-((3aS,6S,6aR)-6-amino-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-di-methyl-1-oxobutan-2-yl)-4-(4-cyclopropylpiperazin-1-yl)benzamide-   N—((S)-1-((3aS,6S,6aR)-6-amino-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-di-methyl-1-oxobutan-2-yl)-4-(4-cyclobutylpiperazin-1-yl)benzamide-   N—((S)-2-((3aS,6S,6aR)-6-amino-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-1-cyclopentyl-2-oxoethyl)-4-(4-propylpiperazin-1-yl)benzamide-   N—((S)-2-((3aS,6S,6aR)-6-amino-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-1-cyclopentyl-2-oxoethyl)-4-(4-cyclopropylpiperazin-1-yl)benzamide-   N—((S)-2-((3aS,6S,6aR)-6-amino-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-1-cyclopentyl-2-oxoethyl)-4-(4-cyclobutylpiperazin-1-yl)benzamide-   N—((S)-2-((3aS,6S,6aR)-6-amino-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-1-cyclohexyl-2-oxoethyl)-4-(4-ethylpiperazin-1-yl)benzamide-   N—((S)-2-((3aS,6S,6aR)-6-amino-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-1-cyclohexyl-2-oxoethyl)-4-(propylpiperazin-1-yl)benzamide-   N—((S)-2-((3aS,6S,6aR)-6-amino-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-1-cyclohexyl-2-oxoethyl)-4-(isopropylpiperazin-1-yl)benzamide-   N—((S)-2-((3aS,6S,6aR)-6-amino-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-1-cyclohexyl-2-oxoethyl)-4-(cyclopropylpiperazin-1-yl)benzamide-   N—((S)-2-((3aS,6S,6aR)-6-amino-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-1-cyclohexyl-2-oxoethyl)-4-(cyclobutylpiperazin-1-yl)benzamide-   N—((S)-1-((3aS,6S,6aR)-6-(methylamino)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)-4-(4-propylpiperazin-1-yl)benzamide-   4-(4-cyclopropylpiperazin-1-yl)-N—((S)-1-((3aS,6S,6aR)-6-(methylamino)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)benzamide-   4-(4-cyclobutylpiperazin-1-yl)-N—((S)-1-((3aS,6S,6aR)-6-(methylamino)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)benzamide-   4-(1-cyclopropylpiperidin-4-yl)-N—((S)-1-((3aS,6S,6aR)-6-(methylamino)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)benzamide-   4-(1-cyclobutylpiperidin-4-yl)-N—((S)-1-((3aS,6S,6aR)-6-(methylamino)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)benzamide-   N—((S)-1-((3aS,6S,6aR)-6-(methylamino)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)-4-(4-propylpiperazin-1-yl)benzamide-   4-(4-cyclopropylpiperazin-1-yl)-N—((S)-1-((3aS,6S,6aR)-6-(methylamino)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)benzamide-   4-(4-cyclobutylpiperazin-1-yl)-N—((S)-1-((3aS,6S,6aR)-6-(methylamino)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)benzamide-   4-(4-ethylpiperazin-1-yl)-N-((2S,3S)-1-((3aS,6S,6aR)-6-(methylamino)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)benzamide-   N-((2S,3S)-1-((3aS,6S,6aR)-6-(methylamino)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)-4-(4-propylpiperazin-1-yl)benzamide-   4-(4-isopropylpiperazin-1-yl-N-((2S,3S)-1-((3aS,6S,6aR)-6-(methylamino)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)-)benzamide-   4-(4-(2-methoxyethyl)piperazin-1-yl)-N-((2S,3S)-1-((3aS,6S,6aR)-6-(methylamino)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)benzamide-   4-(4-cyclopropylpiperazin-1-yl)-N-((2S,3S)-1-((3aS,6S,6aR)-6-(methylamino)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)benzamide-   4-(4-cyclobutylpiperazin-1-yl)-N-((2S,3S)-1-((3aS,6S,6aR)-6-(methylamino)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)benzamide-   N-((2S,3S)-1-((3aS,6S,6aR)-6-(methylamino)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)-4-(1-propylpiperidin-4-yl)benzamide-   4-(1-isopropylpiperidin-4-yl)-N-((2S,3S)-1-((3aS,6S,6aR)-6-(methylamino)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)benzamide-   4-(1-cyclopropylpiperidin-4-yl)-N-((2S,3S)-1-((3aS,6S,6aR)-6-(methylamino)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)benzamide-   4-(1-cyclobutylpiperidin-4-yl)-N-((2S,3S)-1-((3aS,6S,6aR)-6-(methylamino)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)benzamide-   N—((S)-1-((3aS,6S,6aR)-6-(methylamino)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxobutan-2-yl)-4-(4-propylpiperazin-1-yl)benzamide-   4-(4-cyclopropylpiperazin-1-yl)-N—((S)-1-((3aS,6S,6aR)-6-(methylamino)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxobutan-2-yl)benzamide-   4-(4-cyclobutylpiperazin-1-yl)-N—((S)-1-((3aS,6S,6aR)-6-(methylamino)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxobutan-2-yl)benzamide-   N—((S)-1-((3aS,6S,6aR)-6-(methylamino)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxobutan-2-yl)-4-(1-propylpiperidin-4-yl)benzamide-   4-(1-cyclopropylpiperidin-4-yl)-N—((S)-1-((3aS,6S,6aR)-6-(methylamino)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3′3-di-methyl-1-oxobutan-2-yl)benzamide-   4-(1-cyclobutylpiperidin-4-yl)-N—((S)-1-((3aS,6S,6aR)-6-(methylamino)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-di-methyl-1-oxobutan-2-yl)benzamide-   N—((S)-1-cyclopentyl-2-((3aS,6S,6aR)-6-(methylamino)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-propylpiperazin-1-yl)benzamide-   N—((S)-1-cyclopentyl-2-((3aS,6S,6aR)-6-(methylamino)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-cyclopropylpiperazin-1-yl)benzamide-   4-(4-cyclobutylpiperazin-1-yl)-N—((S)-1-cyclopentyl-2-((3aS,6S,6aR)-6-(methylamino)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)benzamide-   N—((S)-1-cyclopentyl-2-((3aS,6S,6aR)-6-(methylamino)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(1-propylpiperidin-4-yl)benzamide-   N—((S)-1-cyclopentyl-2-((3aS,6S,6aR)-6-(methylamino)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(1-cyclopropylpiperidin-4-yl)benzamide-   4-(1-cyclobutylpiperidin-4-yl)-N—((S)-1-cyclopentyl-2-((3aS,6S,6aR)-6-(methylamino)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)benzamide-   N—((S)-1-cyclohexyl-2-((3aS,6S,6aR)-6-(methylamino)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-ethylpiperazin-1-yl)benzamide-   N—((S)-1-cyclohexyl-2-((3aS,6S,6aR)-6-(methylamino)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-propylpiperazin-1-yl)benzamide-   N—((S)-1-cyclohexyl-2-((3aS,6S,6aR)-6-(methylamino)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-isopropylpiperazin-1-yl)benzamide-   N—((S)-1-cyclohexyl-2-((3aS,6S,6aR)-6-(methylamino)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-cyclopropylpiperazin-1-yl)benzamide-   4-(4-cyclobutylpiperazin-1-yl)-N—((S)-1-cyclohexyl-2-((3aS,6S,6aR)-6-(methylamino)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)benzamide-   N—((S)-1-cyclohexyl-2-((3aS,6S,6aR)-6-(methylamino)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(1-propylpiperidin-4-yl)benzamide-   N—((S)-1-cyclohexyl-2-((3aS,6S,6aR)-6-(methylamino)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(1-cyclopropylpiperidin-4-yl)benzamide-   4-(1-cyclobutylpiperidin-4-yl)-N—((S)-1-cyclohexyl-2-((3aS,6S,6aR)-6-(methylamino)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)benzamide-   4-(4-methylpiperazin-1-yl)-N—((S)-1-((3aS,6S,6aS)-6-(methylthio)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)benzamide-   4-(4-ethylpiperazin-1-yl)-N—((S)-1-((3aS,6S,6aS)-6-(methylthio)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)benzamide-   N—((S)-1-((3aS,6S,6aS)-6-(methylthio)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)-4-(4-propylpiperazin-1-yl)benzamide-   4-(4-isopropylpiperazin-1-yl)-N—((S)-1-((3aS,6S,6aS)-6-(methylthio)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)benzamide-   4-(4-(2-methoxyethyl)piperazin-1-yl)-N—((S)-1-((3aS,6S,6aS)-6-(methylthio)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)benzamide-   4-(4-cyclopropylpiperazin-1-yl)-N—((S)-1-((3aS,6S,6aS)-6-(methylthio)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)benzamide-   4-(4-cyclobutylpiperazin-1-yl)-N—((S)-1-((3aS,6S,6aS)-6-(methylthio)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)benzamide-   4-(1-ethylpiperidin-4-yl)-N—((S)-1-((3aS,6S,6aS)-6-(methylthio)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)benzamide-   N—((S)-1-((3aS,6S,6aS)-6-(methylthio)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)-4-(1-propylpiperidin-4-yl)benzamide-   4-(1-isopropylpiperidin-4-yl)-N—((S)-1-((3aS,6S,6aS)-6-(methylthio)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)benzamide-   4-(1-(2-methoxyethyl)piperidin-4-yl)-N—((S)-1-((3aS,6S,6aS)-6-(methylthio)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)benzamide-   4-(1-cyclopropylpiperidin-4-yl)-N—((S)-1-((3aS,6S,6aS)-6-(methylthio)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)benzamide-   4-(1-cyclobutylpiperidin-4-yl)-N—((S)-1-((3aS,6S,6aS)-6-(methylthio)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)benzamide-   4-(4-methylpiperazin-1-yl)-N—((S)-1-((3aS,6S,6aS)-6-(methylthio)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)benzamide-   4-(4-ethylpiperazin-1-yl)-N—((S)-1-((3aS,6S,6aS)-6-(methylthio)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)benzamide-   N—((S)-1-((3aS,6S,6aS)-6-(methylthio)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)-4-(4-propylpiperazin-1-yl)benzamide-   4-(4-isopropylpiperazin-1-yl)-N—((S)-1-((3aS,6S,6aS)-6-(methylthio)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)benzamide-   4-(4-(2-methoxyethyl)piperazin-1-yl)-N—((S)-1-((3aS,6S,6aS)-6-(methylthio)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)benzamide-   4-(4-cyclopropylpiperazin-1-yl)-N—((S)-1-((3aS,6S,6aS)-6-(methylthio)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)benzamide-   4-(4-cyclobutylpiperazin-1-yl)-N—((S)-1-((3aS,6S,6aS)-6-(methylthio)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)benzamide-   N—((S)-1-((3aS,6S,6aS)-6-(methylthio)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)-4-(1-propylpiperidin-4-yl)benzamide-   4-(1-isopropylpiperidin-4-yl)-N—((S)-1-((3aS,6S,6aS)-6-(methylthio)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)benzamide-   4-(1-cyclopropylpiperidin-4-yl)-N—((S)-1-((3aS,6S,6aS)-6-(methylthio)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)benzamide-   4-(1-cyclobutylpiperidin-4-yl)-N—((S)-1-((3aS,6S,6aS)-6-(methylthio)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)benzamide-   4-(4-methylpiperazin-1-yl)-N-((2S,3S)-1-((3aS,6S,6aS)-6-(methylthio)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)benzamide-   4-(4-ethylpiperazin-1-yl)-N-((2S,3S)-1-((3aS,6S,6aS)-6-(methylthio)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)benzamide-   N-((2S,3S)-1-((3aS,6S,6aS)-6-(methylthio)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)-4-(4-propylpiperazin-1-yl)benzamide-   4-(4-isopropylpiperazin-1-yl)-N-((2S,3S)-1-((3aS,6S,6aS)-6-(methylthio)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)benzamide-   4-(4-(2-methoxyethyl)piperazin-1-yl)-N-((2S,3S)-1-((3aS,6S,6aS)-6-(methylthio)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)benzamide-   4-(4-cyclopropylpiperazin-1-yl)-N-((2S,3S)-1-((3aS,6S,6aS)-6-(methylthio)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)benzamide-   4-(4-cyclobutylpiperazin-1-yl)-N-((2S,3S)-1-((3aS,6S,6aS)-6-(methylthio)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)benzamide-   4-(1-methylpiperidin-4-yl)-N-((2S,3S)-1-((3aS,6S,6aS)-6-(methylthio)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)benzamide-   4-(1-ethylpiperidin-4-yl)-N-((2S,3S)-1-((3aS,6S,6aS)-6-(methylthio)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)benzamide-   N-((2S,3S)-1-((3aS,6S,6aS)-6-(methylthio)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)-4-(1-propylpiperidin-4-yl)benzamide-   4-(1-isopropylpiperidin-4-yl)-N-((2S,3S)-1-((3aS,6S,6aS)-6-(methylthio)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)benzamide-   4-(1-(2-methoxyethyl)piperidin-4-yl)-N-((2S,3S)-1-((3aS,6S,6aS)-6-(methylthio)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)benzamide-   4-(1-cyclopropylpiperidin-4-yl)-N-((2S,3S)-1-((3aS,6S,6aS)-6-(methylthio)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)benzamide-   4-(1-cyclobutylpiperidin-4-yl)-N-((2S,3S)-1-((3aS,6S,6aS)-6-(methylthio)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)benzamide-   4-(4-methylpiperazin-1-yl)-N—((S)-1-((3aS,6S,6aS)-6-(methylthio)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxobutan-2-yl)benzamide-   4-(4-ethylpiperazin-1-yl)-N—((S)-1-((3aS,6S,6aS)-6-(methylthio)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxobutan-2-yl)benzamide-   N—((S)-1-((3aS,6S,6aS)-6-(methylthio)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxobutan-2-yl)-4-(4-propylpiperazin-1-yl)benzamide-   4-(4-isopropylpiperazin-1-yl)-N—((S)-1-((3aS,6S,6aS)-6-(methylthio)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxobutan-2-yl)benzamide-   4-(4-(2-methoxyethyl)piperazin-1-yl)-N—((S)-1-((3aS,6S,6aS)-6-(methylthio)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-di-methyl-1-oxobutan-2-yl)benzamide-   4-(4-cyclopropylpiperazin-1-yl)-N—((S)-1-((3aS,6S,6aS)-6-(methylthio)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxobutan-2-yl)benzamide-   4-(4-cyclobutylpiperazin-1-yl)-N—((S)-1-((3aS,6S,6aS)-6-(methylthio)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxobutan-2-yl)benzamide-   4-(1-ethylpiperidin-4-yl)-N—((S)-1-((3aS,6S,6aS)-6-(methylthio)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxobutan-2-yl)benzamide-   N—((S)-1-((3aS,6S,6aS)-6-(methylthio)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxobutan-2-yl)-4-(1-propylpiperidin-4-yl)benzamide-   4-(1-isopropylpiperidin-4-yl)-N—((S)-1-((3aS,6S,6aS)-6-(methylthio)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxobutan-2-yl)benzamide-   4-(1-cyclopropylpiperidin-4-yl)-N—((S)-1-((3aS,6S,6aS)-6-(methylthio)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxobutan-2-yl)benzamide-   4-(1-cyclobutylpiperidin-4-yl)-N—((S)-1-((3aS,6S,6aS)-6-(methylthio)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxobutan-2-yl)benzamide-   N—((S)-1-cyclopentyl-2-((3aS,6S,6aS)-6-(methylthio)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-methylpiperazin-1-yl)benzamide-   N—((S)-1-cyclopentyl-2-((3aS,6S,6aS)-6-(methylthio)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-ethylpiperazin-1-yl)benzamide-   N—((S)-1-cyclopentyl-2-((3aS,6S,6aS)-6-(methylthio)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-propylpiperazin-1-yl)benzamide-   N—((S)-1-cyclopentyl-2-((3aS,6S,6aS)-6-(methylthio)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-isopropylpiperazin-1-yl)benzamide-   N—((S)-1-cyclopentyl-2-((3aS,6S,6aS)-6-(methylthio)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-(2-methoxyethyl)piperazin-1-yl)benzamide-   N—((S)-1-cyclopentyl-2-((3aS,6S,6aS)-6-(methylthio)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-cyclopropylpiperazin-1-yl)benzamide-   4-(4-cyclobutylpiperazin-1-yl)-N—((S)-1-cyclopentyl-2-((3aS,6S,6aS)-6-(methylthio)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)benzamide-   N—((S)-1-cyclopentyl-2-((3aS,6S,6aS)-6-(methylthio)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(1-methylpiperidin-4-yl)benzamide-   N—((S)-1-cyclopentyl-2-((3aS,6S,6aS)-6-(methylthio)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(1-ethylpiperidin-4-yl)benzamide-   N—((S)-1-cyclopentyl-2-((3aS,6S,6aS)-6-(methylthio)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(1-propylpiperidin-4-yl)benzamide-   N—((S)-1-cyclopentyl-2-((3aS,6S,6aS)-6-(methylthio)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(1-isopropylpiperidin-4-yl)benzamide-   N—((S)-1-cyclopentyl-2-((3aS,6S,6aS)-6-(methylthio)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(1-(2-methoxyethyl)piperidin-4-yl)benzamide-   N—((S)-1-cyclopentyl-2-((3aS,6S,6aS)-6-(methylthio)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(1-cyclopropylpiperidin-4-yl)benzamide-   4-(1-cyclobutylpiperidin-4-yl)-N—((S)-1-cyclopentyl-2-((3aS,6S,6aS)-6-(methylthio)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)benzamide-   N—((S)-1-cyclohexyl-2-((3aS,6S,6aS)-6-(methylthio)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-methylpiperazin-1-yl)benzamide-   N—((S)-1-cyclohexyl-2-((3aS,6S,6aS)-6-(methylthio)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-ethylpiperazin-1-yl)benzamide-   N—((S)-1-cyclohexyl-2-((3aS,6S,6aS)-6-(methylthio)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-propylpiperazin-1-yl)benzamide-   N—((S)-1-cyclohexyl-2-((3aS,6S,6aS)-6-(methylthio)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-isopropylpiperazin-1-yl)benzamide-   N—((S)-1-cyclohexyl-2-((3aS,6S,6aS)-6-(methylthio)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-(2-methoxyethyl)piperazin-1-yl)benzamide-   N—((S)-1-cyclohexyl-2-((3aS,6S,6aS)-6-(methylthio)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-cyclopropylpiperazin-1-yl)benzamide-   4-(4-cyclobutylpiperazin-1-yl)-N—((S)-1-cyclohexyl-2-((3aS,6S,6aS)-6-(methylthio)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)benzamide-   N—((S)-1-cyclohexyl-2-((3aS,6S,6aS)-6-(methylthio)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(1-methylpiperidin-4-yl)benzamide-   N—((S)-1-cyclohexyl-2-((3aS,6S,6aS)-6-(methylthio)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(1-ethylpiperidin-4-yl)benzamide-   N—((S)-1-cyclohexyl-2-((3aS,6S,6aS)-6-(methylthio)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(1-propylpiperidin-4-yl)benzamide-   N—((S)-1-cyclohexyl-2-((3aS,6S,6aS)-6-(methylthio)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(1-isopropylpiperidin-4-yl)benzamide-   N—((S)-1-cyclohexyl-2-((3aS,6S,6aS)-6-(methylthio)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(1-(2-methoxyethyl)piperidin-4-yl)benzamide-   N—((S)-1-cyclohexyl-2-((3aS,6S,6aS)-6-(methylthio)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(1-cyclopropylpiperidin-4-yl)benzamide-   4-(1-cyclobutylpiperidin-4-yl)-N—((S)-1-cyclohexyl-2-((3aS,6S,6aS)-6-(methylthio)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)benzamide-   N—((S)-1-((3aS,6S,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)-4-(4-methylpiperazin-1-yl)benzamide-   N—((S)-1-((3aS,6S,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)-4-(4-ethylpiperazin-1-yl)benzamide-   N—((S)-1-((3aS,6S,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)-4-(4-propylpiperazin-1-yl)benzamide-   N—((S)-1-((3aS,6S,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)-4-(4-isopropylpiperazin-1-yl)benzamide-   N—((S)-1-((3aS,6S,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)-4-(4-(2-methoxyethyl)piperazin-1-yl)benzamide-   N—((S)-1-((3aS,6S,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)-4-(4-cyclopropylpiperazin-1-yl)benzamide-   N—((S)-1-((3aS,6S,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)-4-(4-cyclobutylpiperazin-1-yl)benzamide-   N—((S)-1-((3aS,6S,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)-4-(1-propylpiperidin-4-yl)benzamide-   N—((S)-1-((3aS,6S,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)-4-(1-isopropylpiperidin-4-yl)benzamide-   N—((S)-1-((3aS,6S,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)-4-(1-(2-methoxyethyl)piperidin-4-yl)benzamide-   N—((S)-1-((3aS,6S,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)-4-(1-cyclopropylpiperidin-4-yl)benzamide-   N—((S)-1-((3aS,6S,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)-4-(1-cyclobutylpiperidin-4-yl)benzamide-   N—((S)-1-((3aS,6S,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)-4-(4-methylpiperazin-1-yl)benzamide-   N—((S)-1-((3aS,6S,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)-4-(4-ethylpiperazin-1-yl)benzamide-   N—((S)-1-((3aS,6S,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)-4-(4-propylpiperazin-1-yl)benzamide-   N—((S)-1-((3aS,6S,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)-4-(4-isopropylpiperazin-1-yl)benzamide-   N—((S)-1-((3aS,6S,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)-4-(4-(2-methoxyethyl)piperazin-1-yl)benzamide-   N—((S)-1-((3aS,6S,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)-4-(4-cyclopropylpiperazin-1-yl)benzamide-   N—((S)-1-((3aS,6S,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)-4-(4-cyclobutylpiperazin-1-yl)benzamide-   N—((S)-1-((3aS,6S,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)-4-(1-propylpiperidin-4-yl)benzamide-   N—((S)-1-((3aS,6S,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)-4-(1-cyclopropylpiperidin-4-yl)benzamide-   N—((S)-1-((3aS,6S,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)-4-(1-cyclobutylpiperidin-4-yl)benzamide-   N-((2S,3S)-1-((3aS,6S,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)-4-(4-methylpiperazin-1-yl)benzamide-   N-((2S,3S)-1-((3aS,6S,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)-4-(4-ethylpiperazin-1-yl)benzamide-   N-((2S,3S)-1-((3aS,6S,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)-4-(4-propylpiperazin-1-yl)benzamide-   N-((2S,3S)-1-((3aS,6S,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)-4-(4-isopropylpiperazin-1-yl)benzamide-   N-((2S,3S)-1-((3aS,6S,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)-4-(4-(2-methoxyethyl)piperazin-1-yl)benzamide-   N-((2S,3S)-1-((3aS,6S,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)-4-(4-cyclopropylpiperazin-1-yl)benzamide-   N-((2S,3S)-1-((3aS,6S,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)-4-(4-cyclobutylpiperazin-1-yl)benzamide-   N-((2S,3S)-1-((3aS,6S,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)-4-(1-methylpiperidin-4-yl)benzamide-   N-((2S,3S)-1-((3aS,6S,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)-4-(1-ethylpiperidin-4-yl)benzamide-   N-((2S,3S)-1-((3aS,6S,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)-4-(1-propylpiperidin-4-yl)benzamide-   N-((2S,3S)-1-((3aS,6S,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)-4-(1-isopropylpiperidin-4-yl)benzamide-   N-((2S,3S)-1-((3aS,6S,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)-4-(1-(2-methoxyethyl)piperidin-4-yl)benzamide-   N-((2S,3S)-1-((3aS,6S,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)-4-(1-cyclopropylpiperidin-4-yl)benzamide-   N-((2S,3S)-1-((3aS,6S,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)-4-(1-cyclobutylpiperidin-4-yl)benzamide-   N—((S)-1-((3aS,6S,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxobutan-2-yl)-4-(4-methylpiperazin-1-yl)benzamide-   N—((S)-1-((3aS,6S,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxobutan-2-yl)-4-(4-ethylpiperazin-1-yl)benzamide-   N—((S)-1-((3aS,6S,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxobutan-2-yl)-4-(4-propylpiperazin-1-yl)benzamide-   N—((S)-1-((3aS,6S,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxobutan-2-yl)-4-(4-isopropylpiperazin-1-yl)benzamide-   N—((S)-1-((3aS,6S,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxobutan-2-yl)-4-(4-(2-methoxyethyl)piperazin-1-yl)benzamide-   N—((S)-1-((3aS,6S,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxobutan-2-yl)-4-(4-cyclopropylpiperazin-1-yl)benzamide-   N—((S)-1-((3aS,6S,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxobutan-2-yl)-4-(4-cyclobutylpiperazin-1-yl)benzamide-   N—((S)-1-((3aS,6S,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxobutan-2-yl)-4-(1-propylpiperidin-4-yl)benzamide-   N—((S)-1-((3aS,6S,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxobutan-2-yl)-4-(1-cyclopropylpiperidin-4-yl)benzamide-   N—((S)-1-((3aS,6S,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxobutan-2-yl)-4-(1-cyclobutylpiperidin-4-yl)benzamide-   N—((S)-1-cyclopentyl-2-((3aS,6S,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-methylpiperazin-1-yl)benzamide-   N—((S)-1-cyclopentyl-2-((3aS,6S,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-ethylpiperazin-1-yl)benzamide-   N—((S)-1-cyclopentyl-2-((3aS,6S,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-propylpiperazin-1-yl)benzamide-   N—((S)-1-cyclopentyl-2-((3aS,6S,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-isopropylpiperazin-1-yl)benzamide-   N—((S)-1-cyclopentyl-2-((3aS,6S,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-(2-methoxyethyl)piperazin-1-yl)benzamide-   N—((S)-1-cyclopentyl-2-((3aS,6S,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-cyclopropylpiperazin-1-yl)benzamide-   4-(4-cyclobutylpiperazin-1-yl)-N—((S)-1-cyclopentyl-2-((3aS,6S,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)benzamide-   N—((S)-1-cyclopentyl-2-((3aS,6S,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(1-propylpiperidin-4-yl)benzamide-   N—((S)-1-cyclopentyl-2-((3aS,6S,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(1-cyclopropylpiperidin-4-yl)benzamide-   4-(1-cyclobutylpiperidin-4-yl)-N—((S)-1-cyclopentyl-2-((3aS,6S,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)benzamide-   N—((S)-1-cyclohexyl-2-((3aS,6S,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-methylpiperazin-1-yl)benzamide-   N—((S)-1-cyclohexyl-2-((3aS,6S,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-ethylpiperazin-1-yl)benzamide-   N—((S)-1-cyclohexyl-2-((3aS,6S,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-propylpiperazin-1-yl)benzamide-   N—((S)-1-cyclohexyl-2-((3aS,6S,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-isopropylpiperazin-1-yl)benzamide-   N—((S)-1-cyclohexyl-2-((3aS,6S,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-(2-methoxyethyl)piperazin-1-yl)benzamide-   N—((S)-1-cyclohexyl-2-((3aS,6S,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-cyclopropylpiperazin-1-yl)benzamide-   4-(4-cyclobutylpiperazin-1-yl)-N—((S)-1-cyclohexyl-2-((3aS,6S,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)benzamide-   N—((S)-1-cyclohexyl-2-((3aS,6S,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(1-methylpiperidin-4-yl)benzamide-   N—((S)-1-cyclohexyl-2-((3aS,6S,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(1-ethylpiperidin-4-yl)benzamide-   N—((S)-1-cyclohexyl-2-((3aS,6S,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(1-propylpiperidin-4-yl)benzamide-   N—((S)-1-cyclohexyl-2-((3aS,6S,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(1-isopropylpiperidin-4-yl)benzamide-   N—((S)-1-cyclohexyl-2-((3aS,6S,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(1-(2-methoxyethyl)piperidin-4-yl)benzamide-   N—((S)-1-cyclohexyl-2-((3aS,6S,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(1-cyclopropylpiperidin-4-yl)benzamide-   4-(1-cyclobutylpiperidin-4-yl)-N—((S)-1-cyclohexyl-2-((3aS,6S,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)benzamide-   N—((S)-1-((3aS,6R,6aS)-6-hydroxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)-4-(4-propylpiperazin-1-yl)benzamide-   N—((S)-1-((3aS,6R,6aS)-6-hydroxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)-4-(4-isopropylpiperazin-1-yl)benzamide-   4-(4-cyclopropylpiperazin-1-yl)-N—((S)-1-((3aS,6R,6aS)-6-hydroxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)benzamide-   4-(4-cyclobutylpiperazin-1-yl)-N—((S)-1-((3aS,6R,6aS)-6-hydroxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)benzamide-   4-(1-cyclopropylpiperidin-4-yl)-N—((S)-1-((3aS,6R,6aS)-6-hydroxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)benzamide-   4-(1-cyclobutylpiperidin-4-yl)-N—((S)-1-((3aS,6R,6aS)-6-hydroxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)benzamide-   N—((S)-1-((3aS,6R,6aS)-6-hydroxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)-4-(4-propylpiperazin-1-yl)benzamide-   N—((S)-1-((3aS,6R,6aS)-6-hydroxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)-4-(4-isopropylpiperazin-1-yl)benzamide-   4-(4-cyclopropylpiperazin-1-yl)-N—((S)-1-((3aS,6R,6aS)-6-hydroxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)benzamide-   4-(4-cyclobutylpiperazin-1-yl)-N—((S)-1-((3aS,6R,6aS)-6-hydroxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)benzamide-   4-(1-cyclopropylpiperidin-4-yl)-N—((S)-1-((3aS,6R,6aS)-6-hydroxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)benzamide-   4-(1-cyclobutylpiperidin-4-yl)-N—((S)-1-((3aS,6R,6aS)-6-hydroxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)benzamide-   4-(4-ethylpiperazin-1-yl)-N-((2S,3S)-1-((3aS,6R,6aS)-6-hydroxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)benzamide-   N-((2S,3S)-1-((3aS,6R,6aS)-6-hydroxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)-4-(4-propylpiperazin-1-yl)benzamide-   N-((2S,3S)-1-((3aS,6R,6aS)-6-hydroxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)-4-(4-isopropylpiperazin-1-yl)benzamide-   4-(4-cyclopropylpiperazin-1-yl)-N-((2S,3S)-1-((3aS,6R,6aS)-6-hydroxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)benzamide-   4-(4-cyclobutylpiperazin-1-yl)-N-((2S,3S)-1-((3aS,6R,6aS)-6-hydroxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)benzamide-   4-(1-cyclopropylpiperidin-4-yl)-N-((2S,3S)-1-((3aS,6R,6aS)-6-hydroxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)benzamide-   4-(1-cyclobutylpiperidin-4-yl)-N-((2S,3S)-1-((3aS,6R,6aS)-6-hydroxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)benzamide-   4-(4-ethylpiperazin-1-yl)-N—((S)-1-((3aS,6R,6aS)-6-hydroxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxobutan-2-yl)benzamide-   ((S)-1-((3aS,6R,6aS)-6-hydroxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxobutan-2-yl)-4-(4-propylpiperazin-1-yl)benzamide-   N—((S)-1-((3aS,6R,6aS)-6-hydroxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxobutan-2-yl)-4-(4-isopropylpiperazin-1-yl)benzamide-   4-(4-cyclopropylpiperazin-1-yl)-N—((S)-1-((3aS,6R,6aS)-6-hydroxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxobutan-2-yl)benzamide-   4-(4-cyclobutylpiperazin-1-yl)-N—((S)-1-((3aS,6R,6aS)-6-hydroxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxobutan-2-yl)benzamide-   4-(1-cyclopropylpiperidin-4-yl)-N—((S)-1-((3aS,6R,6aS)-6-hydroxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxobutan-2-yl)benzamide-   4-(1-cyclobutylpiperidin-4-yl)-N—((S)-1-((3aS,6R,6aS)-6-hydroxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxobutan-2-yl)benzamide-   N—((S)-1-cyclopentyl-2-((3aS,6R,6aS)-6-hydroxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-methylpiperazin-1-yl)benzamide-   N—((S)-1-cyclopentyl-2-((3aS,6R,6aS)-6-hydroxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-ethylpiperazin-1-yl)benzamide-   N—((S)-1-cyclopentyl-2-((3aS,6R,6aS)-6-hydroxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-propylpiperazin-1-yl)benzamide-   N—((S)-1-cyclopentyl-2-((3aS,6R,6aS)-6-hydroxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-isopropylpiperazin-1-yl)benzamide-   N—((S)-1-cyclopentyl-2-((3aS,6R,6aS)-6-hydroxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-(2-methoxyethyl)piperazin-1-yl)benzamide-   N—((S)-1-cyclopentyl-2-((3aS,6R,6aS)-6-hydroxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-cyclopropylpiperazin-1-yl)benzamide-   4-(4-cyclobutylpiperazin-1-yl)-N—((S)-1-cyclopentyl-2-((3aS,6R,6aS)-6-hydroxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)benzamide-   N—((S)-1-cyclopentyl-2-((3aS,6R,6aS)-6-hydroxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(1-propylpiperidin-4-yl)benzamide-   N—((S)-1-cyclopentyl-2-((3aS,6R,6aS)-6-hydroxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(1-isopropylpiperidin-4-yl)benzamide-   N—((S)-1-cyclopentyl-2-((3aS,6R,6aS)-6-hydroxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(1-cyclopropylpiperidin-4-yl)benzamide-   4-(1-cyclobutylpiperidin-4-yl)-N—((S)-1-cyclopentyl-2-((3aS,6R,6aS)-6-hydroxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)benzamide-   N—((S)-1-cyclohexyl-2-((3aS,6R,6aS)-6-hydroxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-methylpiperazin-1-yl)benzamide-   N—((S)-1-cyclohexyl-2-((3aS,6R,6aS)-6-hydroxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-ethylpiperazin-1-yl)benzamide-   N—((S)-1-cyclohexyl-2-((3aS,6R,6aS)-6-hydroxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-propylpiperazin-1-yl)benzamide-   N—((S)-1-cyclohexyl-2-((3aS,6R,6aS)-6-hydroxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-isopropylpiperazin-1-yl)benzamide-   N—((S)-1-cyclohexyl-2-((3aS,6R,6aS)-6-hydroxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-(2-methoxyethyl)piperazin-1-yl)benzamide-   N—((S)-1-cyclohexyl-2-((3aS,6R,6aS)-6-hydroxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-cyclopropylpiperazin-1-yl)benzamide-   4-(4-cyclobutylpiperazin-1-yl)-N—((S)-1-cyclohexyl-2-((3aS,6R,6aS)-6-hydroxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)benzamide-   N—((S)-1-cyclohexyl-2-((3aS,6R,6aS)-6-hydroxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(1-propylpiperidin-4-yl)benzamide-   N—((S)-1-cyclohexyl-2-((3aS,6R,6aS)-6-hydroxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(1-isopropylpiperidin-4-yl)benzamide-   N—((S)-1-cyclohexyl-2-((3aS,6R,6aS)-6-hydroxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(1-cyclopropylpiperidin-4-yl)benzamide-   4-(1-cyclobutylpiperidin-4-yl)-N—((S)-1-cyclohexyl-2-((3aS,6R,6aS)-6-hydroxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)benzamide-   N—((S)-1-((3aS,6R,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)-4-(4-methylpiperazin-1-yl)benzamide-   4-(4-ethylpiperazin-1-yl)-N—((S)-1-((3aS,6R,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)benzamide-   N—((S)-1-((3aS,6R,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)-4-(4-propylpiperazin-1-yl)benzamide-   4-(4-isopropylpiperazin-1-yl)-N—((S)-1-((3aS,6R,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)benzamide-   4-(4-(2-methoxyethyl)piperazin-1-yl)-N—((S)-1-((3aS,6R,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)benzamide-   4-(4-cyclopropylpiperazin-1-yl)-N—((S)-1-((3aS,6R,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)benzamide-   4-(4-cyclobutylpiperazin-1-yl)-N—((S)-1-((3aS,6R,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)benzamide-   4-(1-cyclopropylpiperidin-4-yl)-N—((S)-1-((3aS,6R,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)benzamide-   4-(1-cyclobutylpiperidin-4-yl)-N—((S)-1-((3aS,6R,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)benzamide-   4-(4-ethylpiperazin-1-yl)-N—((S)-1-((3aS,6R,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)benzamide-   N—((S)-1-((3aS,6R,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)-4-(4-propylpiperazin-1-yl)benzamide-   4-(4-isopropylpiperazin-1-yl)-N—((S)-1-((3aS,6R,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)benzamide-   4-(4-(2-methoxyethyl)piperazin-1-yl)-N—((S)-1-((3aS,6R,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)benzamide-   4-(4-cyclopropylpiperazin-1-yl)-N—((S)-1-((3aS,6R,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)benzamide-   4-(4-cyclobutylpiperazin-1-yl)-N—((S)-1-((3aS,6R,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)benzamide-   4-(1-cyclopropylpiperidin-4-yl)-N—((S)-1-((3aS,6R,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)benzamide-   4-(1-cyclobutylpiperidin-4-yl)-N—((S)-1-((3aS,6R,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)benzamide-   N-((2S,3S)-1-((3aS,6R,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)-4-(4-methylpiperazin-1-yl)benzamide-   4-(4-ethylpiperazin-1-yl)-N-((2S,3S)-1-((3aS,6R,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)benzamide-   N-((2S,3S)-1-((3aS,6R,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)-4-(4-propylpiperazin-1-yl)benzamide-   4-(4-isopropylpiperazin-1-yl)-N-((2S,3S)-1-((3aS,6R,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)benzamide-   4-(4-(2-methoxyethyl)piperazin-1-yl)-N-((2S,3S)-1-((3aS,6R,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)benzamide-   4-(4-cyclopropylpiperazin-1-yl)-N-((2S,3S)-1-((3aS,6R,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)benzamide-   4-(4-cyclobutylpiperazin-1-yl)-N-((2S,3S)-1-((3aS,6R,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)benzamide-   4-(1-ethylpiperidin-4-yl)-N-((2S,3S)-1-((3aS,6R,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)benzamide-   N-((2S,3S)-1-((3aS,6R,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)-4-(1-propylpiperidin-4-yl)benzamide-   4-(1-isopropylpiperidin-4-yl)-N-((2S,3S)-1-((3aS,6R,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)benzamide-   4-(1-cyclopropylpiperidin-4-yl)-N-((2S,3S)-1-((3aS,6R,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)benzamide-   4-(1-cyclobutylpiperidin-4-yl)-N-((2S,3S)-1-((3aS,6R,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)benzamide-   N—((S)-1-((3aS,6R,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxobutan-2-yl)-4-(4-methylpiperazin-1-yl)benzamide-   4-(4-ethylpiperazin-1-yl)-N—((S)-1-((3aS,6R,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxobutan-2-yl)benzamide-   N—((S)-1-((3aS,6R,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxobutan-2-yl)-4-(4-propylpiperazin-1-yl)benzamide-   4-(4-isopropylpiperazin-1-yl)-N—((S)-1-((3aS,6R,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxobutan-2-yl)benzamide-   N—((S)-1-((3aS,6R,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxobutan-2-yl)-4-(4-(2-methoxyethyl)piperazin-1-yl)benzamide-   4-(4-cyclopropylpiperazin-1-yl)-N—((S)-1-((3aS,6R,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxobutan-2-yl)benzamide-   4-(4-cyclobutylpiperazin-1-yl)-N—((S)-1-((3aS,6R,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxobutan-2-yl)benzamide-   4-(1-cyclopropylpiperidin-4-yl)-N—((S)-1-((3aS,6R,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxobutan-2-yl)benzamide-   4-(1-cyclobutylpiperidin-4-yl)-N—((S)-1-((3aS,6R,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxobutan-2-yl)benzamide-   N—((S)-1-cyclopentyl-2-((3aS,6R,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-methylpiperazin-1-yl)benzamide-   N—((S)-1-cyclopentyl-2-((3aS,6R,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-ethylpiperazin-1-yl)benzamide-   N—((S)-1-cyclopentyl-2-((3aS,6R,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-propylpiperazin-1-yl)benzamide-   N—((S)-1-cyclopentyl-2-((3aS,6R,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-isopropylpiperazin-1-yl)benzamide-   N—((S)-1-cyclopentyl-2-((3aS,6R,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-(2-methoxyethyl)piperazin-1-yl)benzamide-   N—((S)-1-cyclopentyl-2-((3aS,6R,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-cyclopropylpiperazin-1-yl)benzamide-   4-(4-cyclobutylpiperazin-1-yl)-N—((S)-1-cyclopentyl-2-((3aS,6R,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)benzamide-   N—((S)-1-cyclopentyl-2-((3aS,6R,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(1-cyclopropylpiperidin-4-yl)benzamide-   4-(1-cyclobutylpiperidin-4-yl)-N—((S)-1-cyclopentyl-2-((3aS,6R,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)benzamide-   N—((S)-1-cyclohexyl-2-((3aS,6R,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-methylpiperazin-1-yl)benzamide-   N—((S)-1-cyclohexyl-2-((3aS,6R,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-ethylpiperazin-1-yl)benzamide-   N—((S)-1-cyclohexyl-2-((3aS,6R,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-propylpiperazin-1-yl)benzamide-   N—((S)-1-cyclohexyl-2-((3aS,6R,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-isopropylpiperazin-1-yl)benzamide-   N—((S)-1-cyclohexyl-2-((3aS,6R,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-(2-methoxyethyl)piperazin-1-yl)benzamide-   N—((S)-1-cyclohexyl-2-((3aS,6R,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-cyclopropylpiperazin-1-yl)benzamide-   4-(4-cyclobutylpiperazin-1-yl)-N—((S)-1-cyclohexyl-2-((3aS,6R,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)benzamide-   N—((S)-1-cyclohexyl-2-((3aS,6R,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(1-ethylpiperidin-4-yl)benzamide-   N—((S)-1-cyclohexyl-2-((3aS,6R,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(1-propylpiperidin-4-yl)benzamide-   N—((S)-1-cyclohexyl-2-((3aS,6R,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(1-isopropylpiperidin-4-yl)benzamide-   N—((S)-1-cyclohexyl-2-((3aS,6R,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(1-cyclopropylpiperidin-4-yl)benzamide-   4-(1-cyclobutylpiperidin-4-yl)-N—((S)-1-cyclohexyl-2-((3aS,6R,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)benzamide-   N—((S)-1-((3aS,6R,6aR)-6-amino-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)-4-(4-propylpiperazin-1-yl)benzamide-   N—((S)-1-((3aS,6R,6aR)-6-amino-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)-4-(4-cyclopropylpiperazin-1-yl)benzamide-   N—((S)-1-((3aS,6R,6aR)-6-amino-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)-4-(4-cyclobutylpiperazin-1-yl)benzamide-   N-((2S,3S)-1-((3aS,6R,6aR)-6-amino-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)-4-(4-ethylpiperazin-1-yl)benzamide-   N-((2S,3S)-1-((3aS,6R,6aR)-6-amino-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)-4-(4-propylpiperazin-1-yl)benzamide-   N-((2S,3S)-1-((3aS,6R,6aR)-6-amino-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)-4-(4-isopropylpiperazin-1-yl)benzamide-   N-((2S,3S)-1-((3aS,6R,6aR)-6-amino-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)-4-(4-cyclopropylpiperazin-1-yl)benzamide-   N-((2S,3S)-1-((3aS,6R,6aR)-6-amino-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)-4-(4-cyclobutylpiperazin-1-yl)benzamide-   N—((S)-1-((3aS,6R,6aR)-6-amino-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxobutan-2-yl)-4-(4-propylpiperazin-1-yl)benzamide-   N—((S)-1-((3aS,6R,6aR)-6-amino-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxobutan-2-yl)-4-(4-cyclopropylpiperazin-1-yl)benzamide-   N—((S)-1-((3aS,6R,6aR)-6-amino-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxobutan-2-yl)-4-(4-cyclobutylpiperazin-1-yl)benzamide-   N—((S)-2-((3aS,6R,6aR)-6-amino-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-1-cyclopentyl-2-oxoethyl)-4-(4-propylpiperazin-1-yl)benzamide-   N—((S)-2-((3aS,6R,6aR)-6-amino-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-1-cyclopentyl-2-oxoethyl)-4-(4-cyclopropylpiperazin-1-yl)benzamide-   N—((S)-2-((3aS,6R,6aR)-6-amino-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-1-cyclopentyl-2-oxoethyl)-4-(4-cyclobutylpiperazin-1-yl)benzamide-   N—((S)-2-((3aS,6R,6aR)-6-amino-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-1-cyclohexyl-2-oxoethyl)-4-(4-ethylpiperazin-1-yl)benzamide-   N—((S)-2-((3aS,6R,6aR)-6-amino-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-1-cyclohexyl-2-oxoethyl)-4-(4-propylpiperazin-1-yl)benzamide-   N—((S)-2-((3aS,6R,6aR)-6-amino-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-1-cyclohexyl-2-oxoethyl)-4-(4-isopropylpiperazin-1-yl)benzamide-   N—((S)-2-((3aS,6R,6aR)-6-amino-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-1-cyclohexyl-2-oxoethyl)-4-(4-cyclopropylpiperazin-1-yl)benzamide-   N—((S)-2-((3aS,6R,6aR)-6-amino-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-1-cyclohexyl-2-oxoethyl)-4-(4-cyclobutylpiperazin-1-yl)benzamide-   N—((S)-1-((3aS,6R,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)-4-(4-methylpiperazin-1-yl)benzamide-   N—((S)-1-((3aS,6R,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)-4-(4-ethylpiperazin-1-yl)benzamide-   N—((S)-1-((3aS,6R,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)-4-(4-propylpiperazin-1-yl)benzamide-   N—((S)-1-((3aS,6R,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)-4-(4-isopropylpiperazin-1-yl)benzamide-   N—((S)-1-((3aS,6R,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)-4-(4-(2-methoxyethyl)piperazin-1-yl)benzamide-   N—((S)-1-((3aS,6R,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)-4-(4-cyclopropylpiperazin-1-yl)benzamide-   N—((S)-1-((3aS,6R,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)-4-(4-cyclobutylpiperazin-1-yl)benzamide-   N—((S)-1-((3aS,6R,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)-4-(1-propylpiperidin-4-yl)benzamide-   N—((S)-1-((3aS,6R,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)-4-(1-isopropylpiperidin-4-yl)benzamide-   N—((S)-1-((3aS,6R,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)-4-(1-(2-methoxyethyl)piperidin-4-yl)benzamide-   N—((S)-1-((3aS,6R,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)-4-(1-cyclopropylpiperidin-4-yl)benzamide-   N—((S)-1-((3aS,6R,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)-4-(1-cyclobutylpiperidin-4-yl)benzamide-   N—((S)-1-((3aS,6R,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)-4-(4-methylpiperazin-1-yl)benzamide-   N—((S)-1-((3aS,6R,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)-4-(4-ethylpiperazin-1-yl)benzamide-   N—((S)-1-((3aS,6R,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)-4-(4-propylpiperazin-1-yl)benzamide-   N—((S)-1-((3aS,6R,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)-4-(4-isopropylpiperazin-1-yl)benzamide-   N—((S)-1-((3aS,6R,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)-4-(4-(2-methoxyethyl)piperazin-1-yl)benzamide-   N—((S)-1-((3aS,6R,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)-4-(4-cyclopropylpiperazin-1-yl)benzamide-   N—((S)-1-((3aS,6R,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)-4-(4-cyclobutylpiperazin-1-yl)benzamide-   N—((S)-1-((3aS,6R,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)-4-(1-propylpiperidin-4-yl)benzamide-   N—((S)-1-((3aS,6R,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)-4-(1-cyclopropylpiperidin-4-yl)benzamide-   N—((S)-1-((3aS,6R,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)-4-(1-cyclobutylpiperidin-4-yl)benzamide-   N-((2S,3S)-1-((3aS,6R,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)-4-(4-methylpiperazin-1-yl)benzamide-   N-((2S,3S)-1-((3aS,6R,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)-4-(4-ethylpiperazin-1-yl)benzamide-   N-((2S,3S)-1-((3aS,6R,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)-4-(4-propylpiperazin-1-yl)benzamide-   N-((2S,3S)-1-((3aS,6R,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)-4-(4-isopropylpiperazin-1-yl)benzamide-   N-((2S,3S)-1-((3aS,6R,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)-4-(4-(2-methoxyethyl)piperazin-1-yl)benzamide-   N-((2S,3S)-1-((3aS,6R,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)-4-(4-cyclopropylpiperazin-1-yl)benzamide-   N-((2S,3S)-1-((3aS,6R,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)-4-(4-cyclobutylpiperazin-1-yl)benzamide-   N-((2S,3S)-1-((3aS,6R,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)-4-(1-methylpiperidin-4-yl)benzamide-   N-((2S,3S)-1-((3aS,6R,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)-4-(1-ethylpiperidin-4-yl)benzamide-   N-((2S,3S)-1-((3aS,6R,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)-4-(1-propylpiperidin-4-yl)benzamide-   N-((2S,3S)-1-((3aS,6R,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)-4-(1-isopropylpiperidin-4-yl)benzamide-   N-((2S,3S)-1-((3aS,6R,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)-4-(1-(2-methoxyethyl)piperidin-4-yl)benzamide-   N-((2S,3S)-1-((3aS,6R,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)-4-(1-cyclopropylpiperidin-4-yl)benzamide-   N-((2S,3S)-1-((3aS,6R,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)-4-(1-cyclobutylpiperidin-4-yl)benzamide-   N—((S)-1-((3aS,6R,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxobutan-2-yl)-4-(4-methylpiperazin-1-yl)benzamide-   N—((S)-1-((3aS,6R,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxobutan-2-yl)-4-(4-ethylpiperazin-1-yl)benzamide-   N—((S)-1-((3aS,6R,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxobutan-2-yl)-4-(4-propylpiperazin-1-yl)benzamide-   N—((S)-1-((3aS,6R,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxobutan-2-yl)-4-(4-isopropylpiperazin-1-yl)benzamide-   N—((S)-1-((3aS,6R,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxobutan-2-yl)-4-(4-(2-methoxyethyl)piperazin-1-yl)benzamide-   N—((S)-1-((3aS,6R,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxobutan-2-yl)-4-(4-cyclopropylpiperazin-1-yl)benzamide-   N—((S)-1-((3aS,6R,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxobutan-2-yl)-4-(4-cyclobutylpiperazin-1-yl)benzamide-   N—((S)-1-((3aS,6R,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxobutan-2-yl)-4-(1-propylpiperidin-4-yl)benzamide-   N—((S)-1-((3aS,6R,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxobutan-2-yl)-4-(1-cyclopropylpiperidin-4-yl)benzamide-   N—((S)-1-((3aS,6R,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxobutan-2-yl)-4-(1-cyclobutylpiperidin-4-yl)benzamide-   N—((S)-2-((3aS,6R,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-1-cyclopentyl-2-oxoethyl)-4-(4-methylpiperazin-1-yl)benzamide-   N—((S)-2-((3aS,6R,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-1-cyclopentyl-2-oxoethyl)-4-(4-ethylpiperazin-1-yl)benzamide-   N—((S)-2-((3aS,6R,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-1-cyclopentyl-2-oxoethyl)-4-(4-propylpiperazin-1-yl)benzamide-   N—((S)-2-((3aS,6R,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-1-cyclopentyl-2-oxoethyl)-4-(4-isopropylpiperazin-1-yl)benzamide-   N—((S)-2-((3aS,6R,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-1-cyclopentyl-2-oxoethyl)-4-(4-(2-methoxyethyl)piperazin-1-yl)benzamide-   N—((S)-2-((3aS,6R,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-1-cyclopentyl-2-oxoethyl)-4-(4-cyclopropylpiperazin-1-yl)benzamide-   N—((S)-2-((3aS,6R,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-1-cyclopentyl-2-oxoethyl)-4-(4-cyclobutylpiperazin-1-yl)benzamide-   N—((S)-2-((3aS,6R,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-1-cyclopentyl-2-oxoethyl)-4-(1-propylpiperidin-4-yl)benzamide-   N—((S)-2-((3aS,6R,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-1-cyclopentyl-2-oxoethyl)-4-(1-cyclopropylpiperidin-4-yl)benzamide-   N—((S)-2-((3aS,6R,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-1-cyclopentyl-2-oxoethyl)-4-(1-cyclobutylpiperidin-4-yl)benzamide-   N—((S)-2-((3aS,6R,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-1-cyclohexyl-2-oxoethyl)-4-(4-methylpiperazin-1-yl)benzamide-   N—((S)-2-((3aS,6R,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-1-cyclohexyl-2-oxoethyl)-4-(4-ethylpiperazin-1-yl)benzamide-   N—((S)-2-((3aS,6R,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-1-cyclohexyl-2-oxoethyl)-4-(4-propylpiperazin-1-yl)benzamide-   N—((S)-2-((3aS,6R,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-1-cyclohexyl-2-oxoethyl)-4-(4-isopropylpiperazin-1-yl)benzamide-   N—((S)-2-((3aS,6R,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-1-cyclohexyl-2-oxoethyl)-4-(4-(2-methoxyethyl)piperazin-1-yl)benzamide-   N—((S)-2-((3aS,6R,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-1-cyclohexyl-2-oxoethyl)-4-(4-cyclopropylpiperazin-1-yl)benzamide-   N—((S)-2-((3aS,6R,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-1-cyclohexyl-2-oxoethyl)-4-(4-cyclobutylpiperazin-1-yl)benzamide-   N—((S)-2-((3aS,6R,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-1-cyclohexyl-2-oxoethyl)-4-(1-methylpiperidin-4-yl)benzamide-   N—((S)-2-((3aS,6R,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-1-cyclohexyl-2-oxoethyl)-4-(1-ethylpiperidin-4-yl)benzamide-   N—((S)-2-((3aS,6R,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-1-cyclohexyl-2-oxoethyl)-4-(1-propylpiperidin-4-yl)benzamide-   N—((S)-2-((3aS,6R,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-1-cyclohexyl-2-oxoethyl)-4-(1-isopropylpiperidin-4-yl)benzamide-   N—((S)-2-((3aS,6R,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-1-cyclohexyl-2-oxoethyl)-4-(1-(2-methoxyethyl)piperidin-4-yl)benzamide-   N—((S)-2-((3aS,6R,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-1-cyclohexyl-2-oxoethyl)-4-(1-cyclopropylpiperidin-4-yl)benzamide-   N—((S)-2-((3aS,6R,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-1-cyclohexyl-2-oxoethyl)-4-(1-cyclobutylpiperidin-4-yl)benzamide

In one highly preferred embodiment, the compound of the invention isselected from EXAMPLES 1, 2, 4, 5, 6, 7, 8, 13, 14, 15, 16, 22, 27 and38 as described in the accompanying Examples section.

In an even more highly preferred embodiment, the compound of theinvention is selected from EXAMPLES 2, 14 and 22 as described in theaccompanying Examples section.

In a yet even more highly preferred embodiment, the compound of theinvention is selected from EXAMPLES 60, 61 and 75 as described in theaccompanying Examples section.

Pharmaceutical Compositions

A further aspect of the invention relates to a pharmaceuticalcomposition comprising a compound of the invention admixed with one ormore pharmaceutically acceptable diluents, excipients or carriers. Otheractive materials may also be present, as may be considered appropriateor advisable for the disease or condition being treated or prevented.

Even though the compounds of the present invention (including theirpharmaceutically acceptable salts, esters and pharmaceuticallyacceptable solvates) can be administered alone, they will generally beadministered in admixture with a pharmaceutical carrier, excipient ordiluent, particularly for human therapy. The pharmaceutical compositionsmay be for human or animal usage in human and veterinary medicine.

Examples of such suitable excipients for the various different forms ofpharmaceutical compositions described herein may be found in the“Handbook of Pharmaceutical Excipients, 2^(nd) Edition, (1994), Editedby A Wade and P J Weller. The carrier, or, if more than one be present,each of the carriers, must be acceptable in the sense of beingcompatible with the other ingredients of the formulation and notdeleterious to the recipient.

Acceptable carriers or diluents for therapeutic use are well known inthe pharmaceutical art, and are described, for example, in Remington'sPharmaceutical Sciences, Mack Publishing Co. (A. R. Gennaro edit. 1985).

Examples of suitable carriers include lactose, starch, glucose, methylcellulose, magnesium stearate, mannitol, sorbitol and the like. Examplesof suitable diluents include ethanol, glycerol and water.

The choice of pharmaceutical carrier, excipient or diluent can beselected with regard to the intended route of administration andstandard pharmaceutical practice. The pharmaceutical compositions maycomprise as, or in addition to, the carrier, excipient or diluent anysuitable binder(s), lubricant(s), suspending agent(s), coating agent(s),solubilising agent(s).

Examples of suitable binders include starch, gelatin, natural sugarssuch as glucose, anhydrous lactose, free-flow lactose, beta-lactose,corn sweeteners, natural and synthetic gums, such as acacia, tragacanthor sodium alginate, carboxymethyl cellulose and polyethylene glycol.

Examples of suitable lubricants include sodium oleate, sodium stearate,magnesium stearate, sodium benzoate, sodium acetate, sodium chloride andthe like.

Preservatives, stabilizers, dyes and even flavoring agents may beprovided in the pharmaceutical composition. Examples of preservativesinclude sodium benzoate, sorbic acid and esters of p-hydroxybenzoicacid. Antioxidants and suspending agents may be also used.

According to a further aspect of the invention, there is provided aprocess for the preparation of a pharmaceutical or veterinarycomposition as described above, the process comprising bringing theactive compound(s) into association with the carrier, for example byadmixture.

In general, the formulations are prepared by uniformly and intimatelybringing into association the active agent with liquid carriers orfinely divided solid carriers or both, and then if necessary shaping theproduct. The invention extends to methods for preparing a pharmaceuticalcomposition comprising bringing a compound of general formula (I) inconjunction or association with a pharmaceutically or veterinarilyacceptable carrier or vehicle.

Salts/Esters

The compounds of the invention can be present as salts or esters, inparticular pharmaceutically and veterinarily acceptable salts or esters.

Pharmaceutically acceptable salts of the compounds of the inventioninclude suitable acid addition or base salts thereof. A review ofsuitable pharmaceutical salts may be found in Berge et al, J Pharm Sci,66, 1-19 (1977). Salts are formed, for example with strong inorganicacids such as mineral acids, e.g. hydrohalic acids such ashydrochloride, hydrobromide and hydroiodide, sulphuric acid, phosphoricacid sulphate, bisulphate, hemisulphate, thiocyanate, persulphate andsulphonic acids; with strong organic carboxylic acids, such asalkanecarboxylic acids of 1 to 4 carbon atoms which are unsubstituted orsubstituted (e.g., by halogen), such as acetic acid; with saturated orunsaturated dicarboxylic acids, for example oxalic, malonic, succinic,maleic, fumaric, phthalic or tetraphthalic; with hydroxycarboxylicacids, for example ascorbic, glycolic, lactic, malic, tartaric or citricacid; with amino acids, for example aspartic or glutamic acid; withbenzoic acid; or with organic sulfonic acids, such as (C₁-C₄)-alkyl- oraryl-sulfonic acids which are unsubstituted or substituted (for example,by a halogen) such as methane- or p-toluene sulfonic acid. Salts whichare not pharmaceutically or veterinarily acceptable may still bevaluable as intermediates.

Preferred salts include, for example, acetate, trifluoroacetate,lactate, gluconate, citrate, tartrate, maleate, malate, pantothenate,adipate, alginate, aspartate, benzoate, butyrate, digluconate,cyclopentanate, glucoheptanate, glycerophosphate, oxalate, heptanoate,hexanoate, fumarate, nicotinate, palmoate, pectinate,3-phenylpropionate, picrate, pivalate, proprionate, tartrate,lactobionate, pivolate, camphorate, undecanoate and succinate, organicsulphonic acids such as methanesulphonate, ethanesulphonate,2-hydroxyethane sulphonate, camphorsulphonate, 2-naphthalenesulphonate,benzenesulphonate, p-chlorobenzenesulphonate and p-toluenesulphonate;and inorganic acids such as hydrochloride, hydrobromide, hydroiodide,sulphate, bisulphate, hemisulphate, thiocyanate, persulphate, phosphoricand sulphonic acids.

Esters are formed either using organic acids or alcohols/hydroxides,depending on the functional group being esterified. Organic acidsinclude carboxylic acids, such as alkanecarboxylic acids of 1 to 12carbon atoms which are unsubstituted or substituted (e.g., by halogen),such as acetic acid; with saturated or unsaturated dicarboxylic acid,for example oxalic, malonic, succinic, maleic, fumaric, phthalic ortetraphthalic; with hydroxycarboxylic acids, for example ascorbic,glycolic, lactic, malic, tartaric or citric acid; with amino acids, forexample aspartic or glutamic acid; with benzoic acid; or with organicsulfonic acids, such as (C₁-C₄)-alkyl- or aryl-sulfonic acids which areunsubstituted or substituted (for example, by a halogen) such asmethane- or p-toluene sulfonic acid. Suitable hydroxides includeinorganic hydroxides, such as sodium hydroxide, potassium hydroxide,calcium hydroxide, aluminium hydroxide. Alcohols include alkanealcoholsof 1-12 carbon atoms which may be unsubstituted or substituted, e.g. bya halogen).

Enantiomers/Tautomers

In all aspects of the present invention previously discussed, theinvention includes, where appropriate all enantiomers, diastereoisomersand tautomers of the compounds of the invention. The person skilled inthe art will recognise compounds that possess optical properties (one ormore chiral carbon atoms) or tautomeric characteristics. Thecorresponding enantiomers and/or tautomers may be isolated/prepared bymethods known in the art.

Enantiomers are characterised by the absolute configuration of theirchiral centres and described by the R- and S-sequencing rules of Cahn,Ingold and Prelog. Such conventions are well known in the art (e.g. see‘Advanced Organic Chemistry’, 3^(rd) edition, ed. March, J., John Wileyand Sons, New York, 1985).

Compounds of the invention containing a chiral centre may be used as aracemic mixture, an enantiomerically enriched mixture, or the racemicmixture may be separated using well-known techniques and an individualenantiomer may be used alone.

Stereo and Geometric Isomers

Some of the compounds of the invention may exist as stereoisomers and/orgeometric isomers—e.g. they may possess one or more asymmetric and/orgeometric centres and so may exist in two or more stereoisomeric and/orgeometric forms. The present invention contemplates the use of all theindividual stereoisomers and geometric isomers of those inhibitoragents, and mixtures thereof. The terms used in the claims encompassthese forms, provided said forms retain the appropriate functionalactivity (though not necessarily to the same degree).

The present invention also includes all suitable isotopic variations ofthe agent or a pharmaceutically acceptable salt thereof. An isotopicvariation of an agent of the present invention or a pharmaceuticallyacceptable salt thereof is defined as one in which at least one atom isreplaced by an atom having the same atomic number but an atomic massdifferent from the atomic mass usually found in nature. Examples ofisotopes that can be incorporated into the agent and pharmaceuticallyacceptable salts thereof include isotopes of hydrogen, carbon, nitrogen,oxygen, phosphorus, sulphur, fluorine and chlorine such as ²H, ³H, ¹³C,¹⁴C, ¹⁵N, ¹⁷O, ¹⁸O, ³¹P, ³²P, ³⁵S, ¹⁸F and ³⁶Cl, respectively. Certainisotopic variations of the agent and pharmaceutically acceptable saltsthereof, for example, those in which a radioactive isotope such as ³H or¹⁴C is incorporated, are useful in drug and/or substrate tissuedistribution studies. Tritiated, i.e., ³H, and carbon-14, i.e., ¹⁴C,isotopes are particularly preferred for their ease of preparation anddetectability. Further, substitution with isotopes such as deuterium,i.e., ²H, may afford certain therapeutic advantages resulting fromgreater metabolic stability, for example, increased in vivo half-life orreduced dosage requirements and hence may be preferred in somecircumstances. For example, the invention includes compounds of generalformula (I) where any hydrogen atom has been replaced by a deuteriumatom. Isotopic variations of the agent of the present invention andpharmaceutically acceptable salts thereof of this invention cangenerally be prepared by conventional procedures using appropriateisotopic variations of suitable reagents.

Prodrugs

The invention further includes the compounds of the present invention inprodrug form, i.e. covalently bonded compounds which release the activeparent drug according to general formula (I) in vivo. Such prodrugs aregenerally compounds of the invention wherein one or more appropriategroups have been modified such that the modification may be reversedupon administration to a human or mammalian subject. Reversion isusually performed by an enzyme naturally present in such subject, thoughit is possible for a second agent to be administered together with sucha prodrug in order to perform the reversion in vivo. Examples of suchmodifications include ester (for example, any of those described above),wherein the reversion may be carried out be an esterase etc. Other suchsystems will be well known to those skilled in the art.

A prodrug may for example constitute a ketal or hemiketal derivative ofthe exocyclic ketone functionality present in thetetrahydro-furo[3,2-b]pyrrol-3-one scaffold.

Solvates

The present invention also includes solvate forms of the compounds ofthe present invention. The terms used in the claims encompass theseforms.

Polymorphs

The invention further relates to the compounds of the present inventionin their various crystalline forms, polymorphic forms and (an)hydrousforms. It is well established within the pharmaceutical industry thatchemical compounds may be isolated in any of such forms by slightlyvarying the method of purification and or isolation form the solventsused in the synthetic preparation of such compounds.

Assays

Another aspect of the invention relates to the use of a compound of theinvention as defined hereinabove in an assay for identifying furthercandidate compounds that influence the activity of one or cysteineproteinases.

Preferably, the assay is capable of identifying candidate compounds thatare capable of inhibiting one or more CAC1 cysteine proteinases.

More preferably, the assay is a competitive binding assay.

Preferably, the candidate compound is generated by conventional SARmodification of a compound of the invention.

As used herein, the term “conventional SAR modification” refers tostandard methods known in the art for varying a given compound by way ofchemical derivatisation.

Thus, in one aspect, the identified compound may act as a model (forexample, a template) for the development of other compounds. Thecompounds employed in such a test may be free in solution, affixed to asolid support, borne on a cell surface, or located intracellularly. Theabolition of activity or the formation of binding complexes between thecompound and the agent being tested may be measured.

The assay of the present invention may be a screen, whereby a number ofagents are tested. In one aspect, the assay method of the presentinvention is a high through-put screen.

This invention also contemplates the use of competitive drug screeningassays in which neutralising antibodies capable of binding a compoundspecifically compete with a test compound for binding to a compound.

Another technique for screening provides for high throughput screening(HTS) of agents having suitable binding affinity to the substances andis based upon the method described in detail in WO 84/03564.

It is expected that the assay methods of the present invention will besuitable for both small and large-scale screening of test compounds aswell as in quantitative assays.

Preferably, the competitive binding assay comprises contacting acompound of the invention with a cysteine proteinase in the presence ofa known substrate of said enzyme and detecting any change in theinteraction between said cysteine proteinase and said known substrate.

A further aspect of the invention provides a method of detecting thebinding of a ligand to a cysteine proteinase, said method comprising thesteps of:

-   (i) contacting a ligand with cysteine proteinase in the presence of    a known substrate of said enzyme;-   (ii) detecting any change in the interaction between said enzyme and    said known substrate; and wherein said ligand is a compound of the    invention.

One aspect of the invention relates to a process comprising the stepsof:

-   (a) performing an assay method described hereinabove;-   (b) identifying one or more ligands capable of binding to a ligand    binding domain; and-   (c) preparing a quantity of said one or more ligands.

Another aspect of the invention provides a process comprising the stepsof:

-   (a) performing an assay method described hereinabove;-   (b) identifying one or more ligands capable of binding to a ligand    binding domain; and-   (c) preparing a pharmaceutical composition comprising said one or    more ligands.

Another aspect of the invention provides a process comprising the stepsof:

-   (a) performing an assay method described hereinabove;-   (b) identifying one or more ligands capable of binding to a ligand    binding domain;-   (c) modifying said one or more ligands capable of binding to a    ligand binding domain;-   (d) performing the assay method described hereinabove;-   (e) optionally preparing a pharmaceutical composition comprising    said one or more ligands.

The invention also relates to a ligand identified by the methoddescribed hereinabove.

Yet another aspect of the invention relates to a pharmaceuticalcomposition comprising a ligand identified by the method describedhereinabove.

Another aspect of the invention relates to the use of a ligandidentified by the method described hereinabove in the preparation of apharmaceutical composition for use in the treatment of one or moredisorders selected from osteoporosis, Paget's disease, Chagas's disease,malaria, gingival disease such as gingivitis or periodontitis,hypercalaemia, metabolic bone disease and diseases involving matrix orcartilage degradation, such as osteoarthritis, rheumatoid arthritis andneoplastic diseases.

The above methods may be used to screen for a ligand useful as aninhibitor of one or more cysteine proteinases.

Compounds of general formula (I) are useful both as laboratory tools andas therapeutic agents. In the laboratory certain compounds of theinvention are useful in establishing whether a known or newly discoveredcysteine proteinase contributes a critical or at least significantbiochemical function during the establishment or progression of adisease state, a process commonly referred to as ‘target validation’.

According to a further aspect of the invention, there is provided amethod of validating a known or putative cysteine proteinase as atherapeutic target, the method comprising:

(a) assessing the in vitro binding of a compound as described above toan isolated known or putative cysteine proteinase, providing a measureof potency; and optionally, one or more of the steps of:

(b) assessing the binding of the compound to closely related homologousproteinases of the target and general house-keeping proteinases (e.g.trypsin) to provide a measure of selectivity;

(c) monitoring a cell-based functional marker of a particular cysteineproteinase activity, in the presence of the compound; and

(d) monitoring an animal model-based functional marker of a particularcysteine proteinase activity in the presence of the compound.

The invention therefore provides a method of validating a known orputative cysteine proteinase as a therapeutic target. Differingapproaches and levels of complexity are appropriate to the effectiveinhibition and ‘validation’ of a particular target. In the firstinstance, the method comprises assessing the in vitro binding of acompound of general formula (I) to an isolated known or putativecysteine proteinase, providing a measure of ‘potency’. An additionalassessment of the binding of a compound of general formula (I) toclosely related homologous proteinases of the target and generalhouse-keeping proteinases (e.g. trypsin) provides a measure of‘selectivity’. A second level of complexity may be assessed bymonitoring a cell-based functional marker of a particular cysteineproteinase activity, in the presence of a compound of general formula(I). For example, an ‘osteoclast resorption assay’ has been utilised asa cell-based secondary in vitro testing system for monitoring theactivity of cathepsin K and the biochemical effect of proteinaseinhibitors (e.g. see WO-A-9850533). An ‘MHC-II processing—T-cellactivation assay’ has been utilised as a cell-based secondary in vitrotesting system for monitoring the activity of cathepsin S and thebiochemical effect of proteinase inhibitors (Shi, G-P., et al, Immunity,10, 197-206, 1999). When investigating viral or bacterial infectionssuch a marker could simply be a functional assessment of viral (e.g.count of mRNA copies) or bacterial loading and assessing the biochemicaleffect of proteinase inhibitors. A third level of complexity may beassessed by monitoring an animal model-based functional marker of aparticular cysteine proteinase activity, in the presence of a compoundof general formula (I). For example, murine models of Leishmaniainfection, P. vinckei infection, malaria (inhibition of falcipain) andT. cruzi infection (cruzipain), indicate that inhibition of cysteineproteinases that play a key role in pathogen propagation is effective inarresting disease symptoms, ‘validating’ said targets.

The invention therefore extends to the use of a compound of generalformula (I) in the validation of a known or putative cysteine proteinaseas a therapeutic target.

Biological Activity

The compounds of the present invention are structurally distinct fromthe prior art (e.g. WO-A-02057270; Quibell, M. et. al., Bioorg. Med.Chem. 13, 609-625, 2005; Quibell M, et al Bioorg. Med. Chem, 12,5689-5710, 2004) in that a wide range of 6-substituents and analkylpiperazine or alkylpiperidine are an intrinsic feature.Advantageously, compounds of the present invention that contain thiscombination of structural features exhibit surprisingly high efficaciesfor human cathepsin K together with high stability in human plasma (seetable 1). Indeed, all of the compounds prepared to date exhibit potentin vitro inhibition versus human cathepsin K with Ki<50 nM. In contrast,the majority of the eighty-two prior art compounds detailed inWO-A-02057270 were significantly less potent against human cathepsin K(2-35 fold less potent) than the compounds of the present invention andin the majority of examples greater than 1000-fold less potent (forexample see table 2).

Preferably, the compounds exhibit in vitro inhibition versus humancathepsin K with Ki<40 nM, more preferably <30 nM, even more preferably<20 nM, more preferably still <10 nM, and even more preferably <5 nM.The compounds of the invention exhibit high selectivity against othermammalian cathepsins displaying little or no inhibitory activity forcathepsins S, L, B and V at 1 □M compound.

The presently claimed compounds also exhibit desirable pharmacokineticproperties. Without wishing to be bound by theory, it is believed thatthe presence of a piperazine or piperidine ring moiety confers compoundsof formula (I) with one or more of the following: favourable human livermicrosome (HLM) stability, improved plasma stability and/or improvedsolubility, compared with other cathepsin K inhibitors known in the art(for example, those disclosed in WO 02/057270 and prior art compound23/10 detailed in Quibell, M. et. al., Bioorg. Med. Chem. 13, 609-625,2005; Quibell M, et al Bioorg. Med. Chem., 12, 5689-5710, 2004). Inparticular, results have shown that compounds of formula (I) asdescribed herein exhibit surprisingly good stability in human plasma(see table 1, stability at 1 h, 37° C.).

In addition, presently claimed compounds exhibit inhibitory activityversus human osteoclast cells. A highly preferred sub-group of presentlyclaimed compounds exhibit potent osteoclast activity versus human cellsand surprisingly an intrinsic feature of the highly preferred sub-groupis an experimentally determined Log D (pH_(7.4)) greater than 0.8. LogDis an experimentally determined characteristic of a compound that isconsidered to reflect the propensity of a compound to transfer acrossthe lipid core of a membrane. LogD is defined as the logarithm of thedistribution coefficient (D) at a selected pH, usually assumed to bemeasured in octanol/water. Without wishing to be bound by theory, it isbelieved that human osteoclast potency and experimentally determined LogD (pH_(7.4)) can be used as a means of further distinguishing highlypreferred inhibitors of cathepsin K. For example, EXAMPLES 3, 23, 24,25, 26 and 28 which exhibit in vitro potency versus human cathepsin K of3.5 to 15.1 nM and human osteoclast inhibitory potency of 25 to 54% alsoexhibit Log D (pH_(7.4)) of 0.01 to 0.76. In contrast, EXAMPLES 1, 2, 4,5, 6, 7, 8, 13, 14, 15, 16, 22, 27 and 38 which exhibit similar in vitropotency versus human cathepsin K of 3.7 to 16.3 nM, but all exhibit LogD (pH_(7.4)) greater than 0.8, show surprisingly improved humanosteoclast inhibitory potency of 63 to 88%.

Therapeutic Use

Compounds of general formula (I) are useful for the in vivo treatment orprevention of diseases in which participation of a cysteine proteinaseis implicated.

In particular, compounds of general formula I are inhibitors of a widerange of CAC1 cysteinyl proteinases for example cathepsin K, cathepsinS, cathepsin L, cathepsin F, cathepsin B, cathepsin V, cruzipains,falcipains and leismania mexicana CPB proteinase.

Preferably, the compound of general formula I is selective for cathepsinK. As used herein, the term “selective for cathepsin K” means that theinhibitor is selective for cathepsin K over one or more other mammalianCAC1 cysteinyl proteinases for example cathepsin S, cathepsin L,cathepsin F, cathepsin B and cathepsin V. Preferably, the inhibitorexhibits a selectivity ratio for cathepsin K over other mammalian CAC1cysteinyl proteinases of greater than 2-fold, more preferably greaterthan 5-fold, more preferably greater than 10-fold, even more preferablygreater than 25-fold, more preferably still, greater than 50-fold or100-fold.

According to a further aspect of the invention, there is provided acompound of general formula (I) for use in medicine, especially forpreventing or treating diseases in which the disease pathology may bemodified by inhibiting a cysteine proteinase.

According to a further aspect of the invention, there is provided theuse of a compound of general formula (I) in the preparation of amedicament for preventing or treating diseases in which the diseasepathology may be modified by inhibiting a cysteine proteinase.

Certain cysteine proteinases function in the normal physiologicalprocess of protein degradation in animals, including humans, e.g. in thedegradation of connective tissue. However, elevated levels of theseenzymes in the body can result in pathological conditions leading todisease. Thus, cysteine proteinases have been implicated in variousdisease states, including but not limited to, infections by Pneumocystiscarinii, Trypsanoma cruzi, Trypsanoma brucei brucei and Crithidiafusiculata; as well as in osteoporosis, osteoarthritis, rheumatoidarthritis, multiple sclerosis, chronic pain, autoimmunity,schistosomiasis, malaria, tumour metastasis, metachromaticleukodystrophy, muscular dystrophy, amytrophy, and the like (seeWO-A-9404172 and EP-A-0603873 and references cited therein).Additionally, a secreted bacterial cysteine proteinase from S. Aureuscalled staphylopain has been implicated as a bacterial virulence factor(Potempa, J., et al. J. Biol. Chem., 262(6), 2664-2667, 1998).

The invention is useful in the prevention and/or treatment of each ofthe disease states mentioned or implied above. The present inventionalso is useful in a methods of treatment or prevention of diseasescaused by pathological levels of cysteine proteinases, particularlycysteine proteinases of the papain superfamily, which methods compriseadministering to an animal, particularly a mammal, most particularly ahuman, in need thereof a compound of the present invention. The presentinvention particularly provides methods for treating diseases in whichcysteine proteinases are implicated, including infections byPneumocystis carinii, Trypsanoma cruzi, Trypsanoma brucei, Leishmaniamexicana, Clostridium histolyticum, Staphylococcus aureus,foot-and-mouth disease virus and Crithidia fusiculata; as well as inosteoporosis, osteoarthritis, rheumatoid arthritis, multiple sclerosis,chronic pain, autoimmunity, schistosomiasis, malaria, tumour metastasis,metachromatic leukodystrophy, muscular dystrophy, amytrophy.

Inhibitors of cathepsin K, particularly cathepsin K-specific compounds,are useful for the treatment of osteoporosis, Paget's disease, gingivaldiseases such as gingivitis and periodontitis, hypercalaemia ofmalignancy, metabolic bone disease, diseases involving matrix orcartilage degradation, in particular osteoarthritis and rheumatoidarthritis and neoplastic diseases.

Preferred features for each aspect of the invention are as for eachother aspect mutatis mutandis.

Administration

The pharmaceutical compositions of the present invention may be adaptedfor rectal, nasal, intrabronchial, topical (including buccal andsublingual), vaginal or parenteral (including subcutaneous,intramuscular, intravenous, intraarterial and intradermal),intraperitoneal or intrathecal administration. Preferably theformulation is an orally administered formulation. The formulations mayconveniently be presented in unit dosage form, i.e., in the form ofdiscrete portions containing a unit dose, or a multiple or sub-unit of aunit dose. By way of example, the formulations may be in the form oftablets and sustained release capsules, and may be prepared by anymethod well known in the art of pharmacy.

Formulations for oral administration in the present invention may bepresented as: discrete units such as capsules, gellules, drops, cachets,pills or tablets each containing a predetermined amount of the activeagent; as a powder or granules; as a solution, emulsion or a suspensionof the active agent in an aqueous liquid or a non-aqueous liquid; or asan oil-in-water liquid emulsion or a water-in-oil liquid emulsion; or asa bolus etc. Preferably, these compositions contain from 1 to 250 mg andmore preferably from 10-100 mg, of active ingredient per dose.

For compositions for oral administration (e.g. tablets and capsules),the term “acceptable carrier” includes vehicles such as commonexcipients e.g. binding agents, for example syrup, acacia, gelatin,sorbitol, tragacanth, polyvinylpyrrolidone (Povidone), methylcellulose,ethylcellulose, sodium carboxymethylcellulose,hydroxypropylmethylcellulose, sucrose and starch; fillers and carriers,for example corn starch, gelatin, lactose, sucrose, microcrystallinecellulose, kaolin, mannitol, dicalcium phosphate, sodium chloride andalginic acid; and lubricants such as magnesium stearate, sodium stearateand other metallic stearates, glycerol stearate stearic acid, siliconefluid, talc waxes, oils and colloidal silica. Flavouring agents such aspeppermint, oil of wintergreen, cherry flavouring and the like can alsobe used. It may be desirable to add a colouring agent to make the dosageform readily identifiable. Tablets may also be coated by methods wellknown in the art.

A tablet may be made by compression or moulding, optionally with one ormore accessory ingredients. Compressed tablets may be prepared bycompressing in a suitable machine the active agent in a free flowingform such as a powder or granules, optionally mixed with a binder,lubricant, inert diluent, preservative, surface-active or dispersingagent. Moulded tablets may be made by moulding in a suitable machine amixture of the powdered compound moistened with an inert liquid diluent.The tablets may be optionally be coated or scored and may be formulatedso as to provide slow or controlled release of the active agent.

Other formulations suitable for oral administration include lozengescomprising the active agent in a flavoured base, usually sucrose andacacia or tragacanth; pastilles comprising the active agent in an inertbase such as gelatin and glycerin, or sucrose and acacia; andmouthwashes comprising the active agent in a suitable liquid carrier.

Other forms of administration comprise solutions or emulsions which maybe injected intravenously, intraarterially, intrathecally,subcutaneously, intradermally, intraperitoneally or intramuscularly, andwhich are prepared from sterile or sterilisable solutions. Injectableforms typically contain between 10-1000 mg, preferably between 10-250mg, of active ingredient per dose.

The pharmaceutical compositions of the present invention may also be inform of suppositories, pessaries, suspensions, emulsions, lotions,ointments, creams, gels, sprays, solutions or dusting powders.

An alternative means of transdermal administration is by use of a skinpatch. For example, the active ingredient can be incorporated into acream consisting of an aqueous emulsion of polyethylene glycols orliquid paraffin. The active ingredient can also be incorporated, at aconcentration of between 1 and 10% by weight, into an ointmentconsisting of a white wax or white soft paraffin base together with suchstabilisers and preservatives as may be required.

Dosage

A person of ordinary skill in the art can easily determine anappropriate dose of one of the instant compositions to administer to asubject without undue experimentation. Typically, a physician willdetermine the actual dosage which will be most suitable for anindividual patient and it will depend on a variety of factors includingthe activity of the specific compound employed, the metabolic stabilityand length of action of that compound, the age, body weight, generalhealth, sex, diet, mode and time of administration, rate of excretion,drug combination, the severity of the particular condition, and theindividual undergoing therapy. The dosages disclosed herein areexemplary of the average case. There can of course be individualinstances where higher or lower dosage ranges are merited, and such arewithin the scope of this invention.

In accordance with this invention, an effective amount of a compound ofgeneral formula (I) may be administered to inhibit the proteinaseimplicated with a particular condition or disease. Of course, thisdosage amount will further be modified according to the type ofadministration of the compound. For example, to achieve an “effectiveamount” for acute therapy, parenteral administration of a compound ofgeneral formula (I) is preferred. An intravenous infusion of thecompound in 5% dextrose in water or normal saline, or a similarformulation with suitable excipients, is most effective, although anintramuscular bolus injection is also useful. Typically, the parenteraldose will be about 0.01 to about 100 mg/kg; preferably between 0.1 and20 mg/kg, in a manner to maintain the concentration of drug in theplasma at a concentration effective to inhibit a cysteine proteinase.The compounds may be administered one to four times daily at a level toachieve a total daily dose of about 0.4 to about 400 mg/kg/day. Theprecise amount of an inventive compound which is therapeuticallyeffective, and the route by which such compound is best administered, isreadily determined by one of ordinary skill in the art by comparing theblood level of the agent to the concentration required to have atherapeutic effect. Prodrugs of compounds of the present invention maybe prepared by any suitable method. For those compounds in which theprodrug moiety is a ketone functionality, specifically ketals and/orhemiketals, the conversion may be effected in accordance withconventional methods.

The compounds of this invention may also be administered orally to thepatient, in a manner such that the concentration of drug is sufficientto inhibit bone resorption or to achieve any other therapeuticindication as disclosed herein. Typically, a pharmaceutical compositioncontaining the compound is administered at an oral dose of between about0.1 to about 50 mg/kg in a manner consistent with the condition of thepatient. Preferably the oral dose would be about 0.5 to about 20 mg/kg.

No unacceptable toxicological effects are expected when compounds of thepresent invention are administered in accordance with the presentinvention. The compounds of this invention, which may have goodbioavailability, may be tested in one of several biological assays todetermine the concentration of a compound which is required to have agiven pharmacological effect.

Combinations

In a particularly preferred embodiment, the one or more compounds of theinvention are administered in combination with one or more other activeagents, for example, existing drugs available on the market. In suchcases, the compounds of the invention may be administered consecutively,simultaneously or sequentially with the one or more other active agents.

Drugs in general are more effective when used in combination. Inparticular, combination therapy is desirable in order to avoid anoverlap of major toxicities, mechanism of action and resistancemechanism(s). Furthermore, it is also desirable to administer most drugsat their maximum tolerated doses with minimum time intervals betweensuch doses. The major advantages of combining chemotherapeutic drugs arethat it may promote additive or possible synergistic effects throughbiochemical interactions and also may decrease the emergence ofresistance.

Beneficial combinations may be suggested by studying the inhibitoryactivity of the test compounds with agents known or suspected of beingvaluable in the treatment of a particular disorder. This procedure canalso be used to determine the order of administration of the agents,i.e. before, simultaneously, or after delivery. Such scheduling may be afeature of all the active agents identified herein.

Synthesis Synthesis of 5,5-Bicyclic Core

One aspect of the invention relates to a process of preparing a compoundof formula (I) as defined above, said process comprising converting acompound of formula (II), where R⁵ is a protecting group, into acompound of formula (I)

In one preferred embodiment, protecting group R⁵ is selected frombenzyloxycarbonyl, tert-butoxycarbonyl, fluoren-9-ylmethoxycarbonyl,1-(biphenyl-4-yl)-1-methylethoxycarbonyl,α,α-dimethyl-3,5-dimethoxylbenzyloxycarbonyl,p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, allyloxycarbonyland trichloroethoxycarbonyl.

In one particularly highly preferred embodiment of the invention, R⁵ isbenzyloxycarbonyl, tert-butoxycarbonyl (Boc) orflouren-9-ylmethoxycarbonyl (Fmoc).

In one preferred embodiment, the process of the invention comprises thestep of converting a compound of formula (III) into a compound offormula (II)

Any suitable oxidising agent may be used to convert the secondaryalcohol group of (III) into the corresponding ketone (II). Suitableoxidising agents will be familiar to the skilled artisan. By way ofexample, the oxidation may be carried out via a Dess-Martin periodinanereaction [Dess, D. B. et al, J. Org. Chem. 1983, 48, 4155; Dess, D. B.et al, J. Am. Chem. Soc. 1991, 113, 7277], or via a Swern oxidation[Mancuso, A. J. et al, J. Org. Chem. 1978, 43, 2480]. Alternatively, theoxidation can be carried out using SO₃/pyridine/Et₃N/DMSO [Parith, J. R.et al, J. Am. Chem. Soc. 1967, 5505; U.S. Pat. No. 3,444,216, Parith, J.R. et al], P₂O₅/DMSO or P₂O₅/Ac₂O [Christensen, S. M. et al, OrganicProcess Research and Development, 2004, 8, 777]. Other alternativeoxidation reagents include activated dimethyl sulphoxide [Mancuso, A.J., Swern, D. J., Synthesis, 1981, 165], pyridinium chlorochromate[Pianeatelli, G. et al, Synthesis, 1982, 245] and Jones' reagent [Vogel,A, I., Textbook of Organic Chemistry, 6^(th) Edition].

More preferably, the process comprises treating a compound of formula(III) with Dess-Martin periodinane. Preferably, the reaction is carriedout using dichloromethane as solvent.

In a more preferred embodiment the process of the invention comprisesthe step of converting a compound of formula (IV) into a compound offormula (III)

In an even more preferred embodiment the process of the inventioncomprises the step of converting a compound of formula (IVa) into acompound of formula (IIIa) or a compound of formula (IVb) into acompound of formula (IIIb)

For compounds of formulae (IIIa) and (IIIb) wherein R¹ or R² are azide,it is preferred the R⁵ protecting group is benzyloxycarbonyl (Cbz) andthe displacement of tosylate is typically performed with sodium azide inDMF at elevated temperature, typically greater than 100° C. The azidoanalogues provide access to 6-amino analogues (e.g. see Scheme 13).

For compounds of formulae (IIIa) and (IIIb) wherein R¹ or R² arethiomethyl, it is preferred that the R⁵ protecting group istert-butoxycarbonyl (Boc) and the displacement of tosylate is typicallyperformed with sodium thiomethoxide [CAS 5188-07-8] in DMF at elevatedtemperature, typically greater than 90° C. One skilled in the art willappreciate that use of alternative thioalkyl reagents provides access toother 6-alkylsulphide analogues (formulae III, R¹ or R² is SR⁶ whereinR⁶ is as previously defined).

Oxidation of the 6-alkylsulphide analogues of formulae (IIIa) and (IIIb)may provide access to the 6-alkylsulphoxides (formulae III, R¹ or R² isSOR⁸ wherein R⁸ is as previously defined) and 6-alkylsulphones (formulaeIII, R¹ or R² is SO₂R⁸ wherein R⁸ is as previously defined).

For compounds of formulae (IIIa) and (IIIb) wherein R¹ or R² aremethylamino, it is preferred the R⁵ protecting group isbenzyloxycarbonyl (Cbz) and the displacement of tosylate is typicallyperformed with methylamine in ethanol with heat. One skilled in the artwill appreciate that use of alternative alkylamine reagents providesaccess to other 6-alkylamino analogues (formulae III, R¹ or R² is NR⁶R⁷wherein R⁶ and R⁷ are as previously defined). Also, within NR⁶R⁷ wheneither R⁶ or R⁷ are hydrogen, it is preferred that the secondary aminofunction is further protected, for example with the tert-butoxycarbonylgroup, providing compounds of formulae (IIIa) or (IIIb) wherein R⁵ isCbz and R¹ or R² are BocNR⁶.

Compounds of formulae (IIIa) and (IIIb) wherein R¹ or R² are alkoxy(OR⁶) can be prepared by direct synthesis (e.g. see scheme 11).Alternatively, for example the R¹=ethoxy analogue can be prepared bydisplacement of tosylate of formula (IVa) where it is preferred that theR⁵ protecting group is tert-butoxycarbonyl (Boc). Displacement istypically performed with sodium ethoxide in ethanol with heat. Oneskilled in the art will appreciate that use of alternative alkoxyreagents provides access to other 6-alkoxy analogues (formulae III, R¹or R² is OR⁶ wherein R⁶ is as previously defined).

In one preferred embodiment the process of the invention comprises thestep of converting a compound of formula (V) into a compound of formula(IV)

More preferably, the process comprises treating a compound of formula(V) with sodium hydride. Preferably, the reaction is carried out in THF.

In an alternative preferred embodiment of the invention, theintra-molecular cyclisation of compound (V) is induced by removal of theprotecting group R⁵. Preferably, for this embodiment, R⁵ isbenzyloxycarbonyl (Cbz), and the process comprises hydrogenating acompound of formula (V) in the presence of a palladium catalyst.

In one preferred embodiment the process of the invention comprises thestep of converting a compound of formula (VI) into a compound of formula(V)

In one preferred embodiment, the oxidising agent is mCPBA.

In another preferred embodiment, the oxidising agent is a dioxirane.

The use of dioxiranes as oxidising agents is well documented in theliterature [see (a) Hodgson, D. M. et al, Synlett, 310 (2002); (b) Adam,W. et al, Acc. Chem. Res. 22, 205, (1989); (c) Yang, D. et al, J. Org.Chem., 60, 3887, (1995); (d) Mello, R. et al, J. Org. Chem., 53, 3890,(1988); (e) Curci, R. et al, Pure & Appl. Chem., 67(5), 811 (1995); (f)Emmons, W. D. et al, J. Amer. Chem. Soc. 89, (1955)].

Preferably, the dioxirane is generated in situ by the reaction of KHSO₅with a ketone. However, the oxidation step can also be carried out usingan isolated dioxirane, for example a stock solution of the dioxiraneformed from acetone.

More preferably, the dioxirane is generated in situ using Oxone®, whichis a commercially available oxidising agent containing KHSO₅ as theactive ingredient.

Thus, in one preferred embodiment, the claimed process involves the insitu epoxidation of a compound of formula (VI) using Oxone®(2KHSO₅KHSO₄.K₂SO₄) and a ketone co-reactant.

As mentioned above, the active ingredient of Oxone® is potassiumperoxymonosulfate, KHSO₅ [CAS-RN 10058-23-8], commonly known aspotassium monopersulfate, which is present as a component of a triplesalt with the formula 2KHSO₅.KHSO₄.K₂SO₄ [potassium hydrogenperoxymonosulfate sulfate (5:3:2:2), CAS-RN 70693-62-8; commerciallyavailable from DuPont]. The oxidation potential of Oxone® is derivedfrom its peracid chemistry; it is the first neutralization salt ofperoxymonosulfuric acid H₂SO₅ (also known as Caro's acid).K⁺⁻O—S(═O)₂(—OOH)

Potassium Monopersulfate

Under slightly basic conditions (pH 7.5-8.0), persulfate reacts with theketone co-reactant to form a three membered cyclic peroxide (adioxirane) in which both oxygens are bonded to the carbonyl carbon ofthe ketone. The cyclic peroxide so formed then epoxidises the compoundof formula VI by syn specific oxygen transfer to the alkene bond.

Preferably, the ketone is of formula (XIX)

wherein R^(a) and R^(b) are each independently alkyl, aryl, haloalkyl orhaloaryl.

Where R^(a) and/or R^(b) are alkyl, the alkyl group may be a straightchain or branched alkyl group. Preferably, the alkyl group is a C₁₋₂₀alkyl group, more preferably a C₁₋₁₅, more preferably still a C₁₋₁₂alkyl group, more preferably still, a C₁₋₈ or C₁₋₆ alkyl group, morepreferably a C₁₋₄ alkyl group. Particularly preferred alkyl groupsinclude, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl,tert-butyl, pentyl and hexyl.

As used herein, the term “haloalkyl” refers to an alkyl group asdescribed above in which one or more hydrogens are replaced by halo.

Where R^(a) and/or R^(b) are aryl, the aryl group is typically a C₆₋₁₂aromatic group. Preferred examples include phenyl and naphthyl etc.

As used herein, the term “haloaryl” refers to an aryl group as describedabove in which one or more hydrogens are replaced by halo.

By way of example, the reaction of KHSO₅ (Oxone®) with a ketone offormula XVI would form a dioxirane of formula:

wherein R^(a) and R^(b) are as defined above.

More preferably, R^(a) and R^(b) are each independently alkyl orhaloalkyl.

In a highly preferred embodiment, at least one of R^(a) and R^(b) is ahaloalkyl, more preferably, CF₃ or CF₂CF₃.

In one preferred embodiment, R^(a) and R^(b) are each independentlymethyl or trifluoromethyl.

In one preferred embodiment of the invention, the ketone is selectedfrom acetone and a 1,1,1-trifluoroalkyl ketone.

In a more preferred embodiment of the invention, the trifluoroalkylketone is 1,1,1-trifluoroacetone or 1,1,1-trifluoro-2-butanone, morepreferably 1,1,1-trifluoro-2-butanone.

In one preferred embodiment the process of the invention comprises thestep of converting a compound of formula (VII) into a compound offormula (VI)

Preferably the process comprises treating a compound of formula (VII)with tosyl chloride in pyridine. Alternatively the process comprisestreating a compound of formula (VII) with tosyl chloride indichloromethane and triethylamine.

In one preferred embodiment the process of the invention comprises thestep of converting a compound of formula (VIII) into a compound offormula (VII)

where W is halogen or tosyl.

Preferably, this step comprises the steps of:

-   (a) reacting a compound of formula (VIII), where W is halogen or    OTs, with aqueous ammonia and alcohol; and-   (b) converting the product formed in step (a) to a compound of    formula (VII).

Preferably, steps (a) and (b) of the above process are a one-potprocess.

In one particularly preferred embodiment, R⁵ is benzyloxycarbonyl, andstep (b) comprises treating the mixture formed in step (a) withbenzyloxycarbonyl chloride.

Preferably, W is I, Br or OTs, more preferably, Br or OTs, even morepreferably OTs.

Preferably, the alcohol is isopropyl alcohol or ethanol.

In one preferred embodiment of the invention, said compound of formulaVIII is prepared from a compound of formula IX

Preferably, the above process comprises treating said compound offormula IX with methyl lithium.

More preferably, compound of formula IX is compound 47 and compound offormula VIII is compound 14; or compound of formula IX is compound 46and compound of formula VIII is compound 13. Treatment ofmonobromotosylates 46 or 47 with zinc dust at room temperature inorganic/aqueous mixtures (most preferably an isopropanol,tetrahydrofuran, water, ammonium chloride mixture) provides alcohols 13and 14 respectively in high yield. Additionally, completion of theone-pot conversion gives alcohols VIIa and VIIb with definedstereochemistry and in high yield.

Commencing from the commercially available sugars isomannide andisosorbide, the present invention also provides facile preparation ofmonobromotosylates 46 and 47 One highly preferred preparation is shownbelow in Scheme 15

Isosorbide (43) is converted to the di-tosylate (42) which is obtainedfollowing recrystallisation from methanol in 97% yield. Mono-brominationis effected by 2.5 eq lithium bromide in DMSO (or DMF) with temperaturecontrol 110° C.→120° C. The product bromide is isolated followingextractive work-up and purification either by column chromatography(74%) or attractive for large scale by recrystallisation from methanolgiving a first crop of 55% plus mother liquors containing good qualitymaterial that may be pooled from batch runs and purified later. Thus,preparation of monobromotosylate (47) with defined stereochemistry bymethods in Scheme 15 is attractive for large scale applications.Treatment of monobromotosylate (47) with zinc dust at room temperaturein organic/aqueous mixtures (most preferably an isopropanol,tetrahydrofuran, water, ammonium chloride mixture) provides alcohol (14)which is derivatised as the Cbz compound (18) through one potconversion.

Treatment of isomannide (40) (Scheme 16) with tosylchloride (2.2 eq) ina bi-phasic potassium hydroxide/dichloromethane/carbon tetrachloridemixture at 0° C. gives ditosylate (39) in 48% yield following simplefiltration and trituration with methanol. Alternatively, treatment ofisomannide (40) with tosylchloride (0.5 eq) in a bi-phasic potassiumhydroxide/dichloromethane/carbon tetrachloride mixture at 0° C. givesmonotosylate in 38% yield following simple extraction andre-crystallisation from carbon tetrachloride (conditions as described inU.S. Pat. No. 6,858,632). Although the monotosylate can be obtained inhigher yield by treatment of isomannide (40) with tosylchloride inpyridine, purification currently requires column chromatography whichmay becomes undesirable at large scale. Monobromotosylate (46) may thenbe prepared by treatment of ditosylate (39) with lithium bromide in DMF(29% yield following chromatography) or by treatment of monotosylateunder Mitsunobu conditions with carbon tetrabromide (63% yield followingchromatography). Treatment of monobromotosylate (46) with zinc dust atroom temperature in organic/aqueous mixtures (most preferably anisopropanol, tetrahydrofuran, water, ammonium chloride mixture) providesalcohol (13) which is derivatised as the Cbz compound (17) through onepot conversion.

In one highly preferred embodiment of the invention, the 5,5-bicyliccore is prepared in accordance with the steps set forth in Scheme 1below:

The alcohol functionality of (18) may be derivatised as the para-toluenesulphonate (Ts) giving(R)-2-(benzyloxycarbonylamino)-1-((S)-2,5-dihydrofuran-2-yl)ethyl4-methylbenzenesulfonate (32b) which proceeds through the anti-epoxide(R)-2-(benzyloxycarbonylamino)-1-((1S,2S,5S)-3,6-dioxabicyclo[3.1.0]hexan-2-yl)ethyl4-methylbenzenesulphonate (33b). Hydrogenation of tosylate (33b)provides free amine that undergoes intramolecular cyclisation. Urethaneprotection of the secondary amine of the bicyclic intermediate gives(3R,3aR,6R,6aS)-benzyl3-hydroxy-6-(tosyloxy)tetrahydro-2H-furo[3,2-b]pyrrole-4(5H)-carboxylate(34b) or (3R,3aR,6R,6aS)-tert-butyl3-hydroxy-6-(tosyloxy)tetrahydro-2H-furo[3,2-b]pyrrole-4(5H)-carboxylate(35b).

Advantageously, the epoxidation to give the desired anti-epoxide isdirected by the presence of the tosylate group whilst only modeststereoselectivity can be achieved for the corresponding saturatedalkene. Thus, the stereoselectivity of the epoxidation is controlled toallow much higher yields of the desired anti-epoxide.

An analogous reaction scheme can be applied to the enantiomer of (18),namely, benzyl (S)-2-((S)-2,5-dihydrofuran-2-yl)-2-hydroxyethylcarbamate (17), proceeding through the analogous anti-epoxide(S)-2-(benzyloxycarbonylamino)-1-((1S,2S,5S)-3,6-dioxabicyclo[3.1.0]hexan-2-yl)ethyl4-methylbenzenesulphonate (32) (Scheme 2).

The tosyl group of bicyclic intermediates (34), (34b), (35), (35b) canact as a leaving group by employing a suitable nucleophile to provideaccess to the corresponding 6-substituted analogues.

For example, treatment of tosylate (34b) with sodium azide indimethylformamide with heating provides 6-azido analogue(3R,3aR,6S,6aS)-benzyl6-azido-3-hydroxytetrahydro-2H-furo[3,2-b]pyrrole-4(5H)-carboxylate(36b) Scheme 13. Reduction of azide to amine e.g. withtriphenylphosphine/water (e.g. see Mandville, G. et al, J. Org. Chem.,61, 1122, 1996) provides the 6-amino intermediate which is Boc-protectedunder standard Schotten-Baumann conditions providing (37b). Conversionof Cbz to Fmoc-protection and oxidation then provides building blocks(8b) and (8c) that can be utilised in a solid phase method to prepare6-amino analogues of general formula I (R¹═NH₂). An analogous reactionsequence may be applied to tosylate (34) to provide the opposite 6-aminoepimers (7b) and (7c) used to prepare 6-amino analogues of generalformula I (R²═NH₂). One skilled in the art will appreciate thattosylates (34), (34b), (35), (35b) are exceptionally versatile analoguesthat open-up synthetic routes to a wide range of 6-substitutedcompounds.

In an alternative embodiment, the alcohol functionality of (17) may beprotected e.g. as the acid labile tert-butyl ether and utilised asdetailed in Scheme 10 below, wherein benzyl(S)-2-((S)-2,5-dihydrofuran-2-yl)-2-hydroxyethyl carbamate (17) proceedsthrough the anti-epoxide benzyl(S)-2-((1S,2R,5S)-3,6-dioxabicyclo[3.1.0]hexan-2-yl)-2-tert-butoxyethylcarbamate (28). An analogous reaction scheme can be applied to benzyl(R)-2-((S)-2,5-dihydrofuran-2-yl)-2-hydroxyethyl carbamate (18)proceeding through the analogous anti-epoxide benzyl(R)-2-((1S,2R,5S)-3,6-dioxabicyclo[3.1.0]hexan-2-yl)-2-tert-butoxyethylcarbamate (28b). Preparation of tert-butyl ethers is typically performedthrough reaction of alcohol with 2-methylpropene in a solvent such asdichloromethane with acid catalysis (e.g. see Wunsch, E. and Jentsch, J.Chem. Ber., 97, 2490, 1964).

As a further alternative, the alcohol functionality of (17) may bederivatised as the methyl ether (30) and utilised as detailed in Scheme11, wherein benzyl (S)-2-((S)-2,5-dihydrofuran-2-yl)-2-hydroxyethylcarbamate (17) proceeds through the anti-epoxide benzyl(S)-2-((1S,2R,5S)-3,6-dioxabicyclo[3.1.0]hexan-2-yl)-2-methoxyethylcarbamate (31). An analogous reaction scheme can be applied to benzyl(R)-2-((S)-2,5-dihydrofuran-2-yl)-2-hydroxyethyl carbamate (18)proceeding through the analogous anti-epoxide benzyl(R)-2-((1S,2R,5S)-3,6-dioxabicyclo[3.1.0]hexan-2-yl)-2-methoxyethylcarbamate (31b). Preparation of methyl ethers is typically performedthrough reaction of alcohol with methyl iodide in a solvent such asacetonitrile with silver (I) oxide catalysis (e.g. see Finch, N. et al,J. Org. Chem., 40, 206, 1975 and refs. cited therein). Alternatively,methyl ethers (30) and (30b) are prepared from alcohols (17) and (18) byreaction with trimethyloxonium fluoroborate, proton sponge[1,8-bis(dimethylamino)naphthalene] and molecular sieves indichloromethane.

Furthermore, the processes of the invention provide compounds of formulaI and intermediates such as compounds of formulae III that contain asubstituent in the 6-position either by direct synthesis (e.g. —OH,6-OMe etc) or by nucleophilic substitution of the 6-tosylates (e.g.compounds 34/35) or 6-mesylates. By way of example, nucleophilicsubstitution of the tosyl analogue (compound 34b) with azide providesthe 6-N₃ analogue (R¹═N₃); one skilled in the art will appreciate thatprotection of the alcohol (e.g. with trimethylsilyl) functionalitywithin this analogue followed by reduction of the 6-azido to 6-aminofunctionality (e.g. as detailed in scheme 13) provides a primary thatmay be N-alkylated (e.g. displacement of an alkyl halide [R⁶-halogen] orreductive amination [with aldehydes such as R^(z)CHO or ketones such asR^(y)R^(z)C═O]) providing compounds wherein R¹═NR⁶R⁷. Alternatively,nucleophilic substitution of the tosyl analogue (compound 34b) withmethylamine provides an additional route towards N-alkylated compoundswherein R¹═NHMe. One skilled in the art will appreciate that use ofalternative alkylamine reagents provides access to other 6-alkylaminoanalogues (formulae III, R¹ or R² is NR⁶R⁷ wherein R⁶ and R⁷ are aspreviously defined). Also, within NR⁶R⁷ when either R⁶ or R⁷ arehydrogen, it is preferred that the secondary amino function is furtherprotected, for example with the tert-butoxycarbonyl group, providingcompounds of formulae (IIIa) or (IIIb) wherein R⁵ is Cbz and R¹ or R² isBocNR⁶. Alternatively, nucleophilic substitution of the tosyl analogue(compounds 34 or 35) with sodium thiomethoxide [CAS 5188-07-8] indimethylacetamide at 90° C. provides the 6-SMe functionalised analogue;one skilled in the art will appreciate that use of alternative thioalkylreagents provides access to other 6-alkylsulphide analogues (formulaeIII, R¹ or R² is SR⁶ wherein R⁶ is as previously defined); additionallyone skilled in the art will appreciate that oxidation of the6-alkylsulphide analogues of formulae (IIIa) and (IIIb) may provideaccess to the 6-alkylsulphoxides (formulae III, R¹ or R² is SOR⁸ whereinR⁸ is as previously defined) and 6-alkylsulphones (formulae III, R¹ orR² is SO₂R⁸ wherein R⁸ is as previously defined). Compounds of formulae(IIIa) and (IIIb) wherein R¹ or R² are alkoxy (OR⁶) can be prepared bydirect synthesis (e.g. as generally detailed in scheme 11).Alternatively, for example the R¹=ethoxy analogue can be prepared bydisplacement of tosylate of formula (IVa) where it is preferred that theR⁵ protecting group is tert-butoxycarbonyl (Boc). Displacement istypically performed with sodium ethoxide in ethanol with heat. Oneskilled in the art will appreciate that use of alternative alkoxyreagents provides access to other 6-alkoxy analogues (formulae III, R¹or R² is OR⁶ wherein R⁶ is as previously defined).

Other displacement reagents may be suitable for access to other6-functionalised analogues, e.g. alkylmetal reagents such asmethyllithium (e.g. see Hanessian, S. et al, J. Am. Chem. Soc., 1990,112(13), 5276-5290) towards the 6-Me analogue; trifluoromethylatingreagents such as trifluoromethyl trimethylsilane (e.g. see Sevenard. D.V. et al, Syn. Lett., 2001, 3, 379-381) or trifluoromethyl magnesiumiodide towards the 6-CF₃ analogue. Thus, these tosyl analogues not onlydirect the stereofacial preference of the epoxidation step, but alsoprovide versatile intermediates to access a host of 6-substitutedbicyclic species.

Synthesis of Compounds of Formula (I)

To those skilled in the practices of organic chemistry, compounds ofgeneral formula (I) may be readily synthesised by a number of chemicalstrategies, performed either in solution or on the solid phase (seeAtherton, E. and Sheppard, R. C. In ‘Solid Phase Peptide Synthesis: APractical Approach’, Oxford University Press, Oxford, U.K. 1989, for ageneral review of solid phase synthesis principles), or a combinationthereof.

Compounds of general formula (I) may be conveniently considered as acombination of three building blocks (P1, P2 and P3) that respectivelyoccupy the S1, S2 and S3 binding sites of the protease (see Berger, Aand Schechter, I., Philos. Trans. R. Soc. Lond. [Biol.], 257, 249-264,1970 for a description of the designation of enzyme S-subsites andsubstrate P-subsites within enzyme-substrate or enzyme-inhibitorcomplexes). The notional concepts of P1, P2 and P3 are used herein forconvenience only and the above-mentioned compounds are intended to bewithin the scope of the invention regardless of binding mode.

A suitably protected and/or activated building block may then beprepared and subsequently chemically bonded (coupled) together withother building blocks to provide compounds of general formula (I).

Compounds of formula (I) may be prepared: (1) by the stepwise additionof P3 and P2 to the bicyclic tetrahydrofuro[3,2-b]pyrrol-3-one core; or(2) by reaction of the bicyclic tetrahydrofuro[3,2-b]pyrrol-3-one corewith a P3-P2 prescursor molecule; or (3) by introducing the P3-P2 groupprior to formation of the bicyclic tetrahydrofuro[3,2-b]pyrrol-3-onecore, i.e. prior to the oxidation step or prior to the intramolecularcyclisation step.

Thus, alternative orders of coupling of the building blocks arepossible, for example P2+P1→P2-P1 then addition of P3→P3-P2-P1 orP3+P2→P3-P2 then addition to P1→P3-P2-P1. Within each of thesecombinations each of the P1, P2 or P3 building blocks may containadditional alternative functionalities that are further transformedfollowing coupling to give the final compound. For example the ketonefunctionality of the P1 building block may be protected as a ketalduring coupling of building blocks and transformed to the final ketoneby hydrolysis following completion of the coupling reactions.Alternatively, the ketone functionality of the P1 building block may beinitially introduced via a lower oxidation state such as thecorresponding alcohol and following completion of the coupling reactionsbe re-introduced by oxidation of the alcohol. Alternatively, the ketonefunctionality of the P1 building block may be protected through asemi-carbazone suitable for solid phase synthesis (e.g. see WO 02/057270and references cited therein) and following completion of the couplingreactions released from the solid phase by acidolytic reaction.

The chemical bond formed by coupling of the building blocks is asecondary amide (P3-P2) or a tertiary amide (P2-P1) that are formedthrough reaction of an activated carboxylic acid with a primary andsecondary amine respectively. Many methods are available for activationof a carboxylic acid prior to coupling to an amine and in principle, anyof these methods may be used herein. Typical carboxylic acid activationmethods are exemplified but not restricted to the azide method, mixedanhydride method (e.g. via isobutylchloroformate), carbodiimide methods(e.g. via dicyclohexylcarbodiimide, diisopropylcarbodiimide,1-ethyl-3-(3′-dimethylamino propyl)carbodiimide), active ester method(e.g. via p-nitrophenyl ester, N-hydroxysuccinic imido ester,pentafluorophenyl ester), uronium method (e.g. via addition of HBTU,PyBop, BOP), carbonyldiimidazole method or via pre-formation of acylfluorides or acyl chlorides. In some instances the coupling reaction maybe enhanced by the addition of a further activation catalyst such as1-hydroxybenzotriazole, or 4-dimethylaminopyridine. A generaldescription of carboxylic acid activation techniques and the use ofactivation additives may be found in Bodanszky, M. ‘Principles ofPeptide Synthesis’, 2^(nd) rev. ed., Springer-Verlag, Berlin, 1993 andreferences cited therein.

The α-amino group of the P2 amino acid building block is usuallyprotected during coupling reactions to the P1 building block to avoidthe formation of undesired self-condensation products. The art ofα-amino protection is well known in peptide chemistry (e.g. seeBodanszky, M. ‘Principles of Peptide Synthesis’, 2^(nd) rev. ed.,Springer-Verlag, Berlin, 1993 and references cited therein) and exampleprotection groups include, but are not limited to,9-fluorenylmethoxycarbonyl (Fmoc), tert-butoxycarbonyl (Boc),benzyloxycarbonyl (Cbz), allyloxycarbonyl (Alloc) andtrichloroethoxycarbonyl (Treoc). The Fmoc group is particularly wellsuited for solid phase syntheses (e.g. see Atherton, E.; Sheppard, R. C.in ‘Solid Phase Peptide Synthesis A Practical Approach’, IRL Press,Oxford, U.K., 1989) typically being removed by treatment with 20% v/vpiperidine in dimethylformamide or 1% v/v1,8-diazabicyclo[5.4.0]undec-7-ene in dimethylformamide. The Boc groupis particularly well suited to solution phase syntheses typically beingremoved by treatment with trifluoroacetic acid based mixtures or HCl indioxane or ethyl acetate. The Cbz group is also particularly well suitedfor solution phase syntheses typically being removed by catalytichydrogenation with hydrogen and palladium catalysis or by treatment withHBr in acetic acid. Once the coupling sequence is complete, anyprotecting groups are removed in whatever manner is dictated by thechoice of protecting groups (for a general description of protectinggroups and their respective stabilities and methods of removal seeGreene, T. W. and Wuts, P. G. M. ‘Protective Groups in OrganicSynthesis’ John Wiley and Sons, New York, 1991 and references therein).

In the simplest example, the entire left hand portion of a compound ofgeneral formula (I) (i.e. P3-P2) as the carboxylic acid can be preparedin solution by traditional organic chemistry methods and coupled toketone, alcohol or ketal intermediates such as compounds (IIb), (IIc)and (IId). Then oxidation of the alcohol intermediate (e.g. Dess-Martinperiodinane in DCM) or acidolytic cleavage of the ketal intermediateprovides compounds of general formula (I). The alcohol oxidation routeis particularly useful when the compound of general formula (I) containsa substituent that is labile to trifluoroacetic acid, this being thefinal reagent used in each of the solid phase syntheses.

Examples of these different coupling tactics have been detailedpreviously (see (i) Quibell, M. et. al., Bioorg. Med. Chem. 13, 609-625,2005. (ii) Wang, Y. et. al., Bioorg. Med. Chem Lett. 15, 1327-1331,2005) and the optimum synthetic route is dependant upon the specificsubstituent combinations of the target compound of general formula (I).

In more detail, one preferred strategy for the synthesis of compounds ofgeneral formula (I) comprises:—

-   (a) Preparation of an appropriately functionalised and protected    bicyclic ketone or bicyclic alcohol building block in solution;-   (b) Attachment of the building block (a) to the solid phase through    a linker that is stable to the conditions of synthesis, but readily    labile to cleavage at the end of a synthesis (see James, I. W.,    Tetrahedron, 55(Report N^(o) 489), 4855-4946, 1999, for examples of    the ‘linker’ function as applied to solid phase synthesis);-   (c) Solid phase organic chemistry (see Brown, R. D. J Chem. Soc.,    Perkin Trans. 1, 19, 3293-3320, 1998), to construct the remainder of    the molecule;-   (d) Compound cleavage from the solid phase into solution; and-   (e) Cleavage work-up and compound analysis.

A second strategy for the synthesis of compounds of general formula (I)comprises:—

-   (a) Preparation of an appropriately functionalised and protected    bicyclic intermediate building block in solution. Preferred    protecting groups for solution phase chemistry are the    9-fluorenylmethoxycarbonyl (Fmoc), Nα-tert-butoxycarbonyl (Boc),    Nα-benzyloxycarbonyl (Cbz) and Nα-allyloxycarbonyl group (Alloc).-   (b) Standard organic chemistry methods for the conversion of    building block obtained in step (a) towards compounds of general    formula (I).

As mentioned above, in one preferred embodiment of the invention,compounds of formula (I) may be prepared using conventional solutionphase chemistry, for example, as described in Quibell, M et al, Bioorg.Med. Chem., 13, 609-625, 2005 (see in particular, Schemes 3 and 4). Thesolution phase strategy is attractive in being able to generate largerquantities of preferred analogues, typically on a multi-gram tomulti-kilogram scale.

In an alternative preferred embodiment of the invention, compounds offormula (I) may be prepared using conventional solid phase chemistry,for example, as described in Quibell M, et al Bioorg. Med. Chem, 12,5689-5710, 2004, see in particular, Scheme 3 and Section 3.2, andreferences cited therein; and Bioorg. Med. Chem, 13, 609-625, 2005, seeScheme 5 and Section 2.2, and references cited therein). The solid phasestrategy is attractive in being able to generate many thousands ofanalogues, typically on a 5-100 mg scale, through established parallelsynthesis methodologies (e.g. see (a) Bastos, M.; Maeji, N. J.; Abeles,R. H. Proc. Natl. Acad. Sci. USA, 92, 6738-6742, 1995).

The synthetic strategy is based on reversible anchorage of the ketonefunctionality via a hydrazide linker bond using general multipintechniques previously described in the art (Watts J. et al, Bioorg. Med.Chem. 12(11), 2903, 2004; Quibell M., et al, Bioorg. Med. Chem.5689-5710, 2004; Grabowksa U. et al, J. Comb. Chem. 2000, 2(5), 475).

Compounds of formula (II) may be utilised in a solid phase synthesis ofinhibitor molecules (1). The solid phase linkage of an aldehyde orketone, has previously been described by a variety of methods (e.g. see(a) James, I. W., 1999, (b) Lee, A., Huang, L., Ellman, J. A., J. Am.Chem. Soc, 121(43), 9907-9914, 1999, (c) Murphy, A. M., et al, J. Am.Chem. Soc, 114, 3156-3157, 1992). A suitable method amenable to thereversible linkage of an alkyl ketone functionality is through acombination of the previously described chemistries. The semicarbazide,4-[[(hydrazinocarbonyl)amino]methyl]cyclohexane carboxylic acid.trifluoroacetate (Murphy, A. M., et al, J. Am. Chem. Soc, 114,3156-3157, 1992), may be utilised as illustrated in Scheme 3,exemplified by linkage of the tetrahydrofuro[3,2-b]pyrrol-3-one (II;R⁵=Fmoc).

Construct (XVII) is prepared through reaction of the linker molecule andthe tetrahydrofuro[3,2-b]pyrrol-3-one II (R⁵=Fmoc) by refluxing inaqueous ethanol/sodium acetate. Standard solid phase techniques (e.g.see Atherton, E. and Sheppard, R. C., 1989) are used to anchor theconstruct to an amino-functionalised solid phase through the freecarboxylic acid functionality of (XVII), providing the loaded construct(XVIII). Loaded construct (XVIII) be reacted with a wide range ofcarboxylic acids available commercially or in the literature, tointroduce the left-hand portion ‘P3-P2’.

The present invention is further described by way of example.

EXAMPLES General Procedures

Solvents were purchased from ROMIL Ltd, U.K. at SpS or Hi-Dry gradeunless otherwise stated. ¹H NMR and ¹³C NMR were obtained on a BrukerDPX400 (400 MHz ¹H frequency and 100 MHz ¹³C frequency; QXI probe) orBruker Avance 500 MHz (TXI probe with ATM) in the solvents indicated.Chemical shifts are expressed in parts per million (□) and arereferenced to residual signals of the solvent. Coupling constants (J)are expressed in Hz. All analytical HPLC were obtained on PhenomenexJupiter C₄, 5□, 300 Å, 250×4.6 mm, using mixtures of solvent A (0.1% aqtrifluoroacetic acid (TFA)) and solvent B (90% acetonitrile/10% solventA) on automated Agilent systems with 215 and/or 254 nm UV detection.Unless otherwise stated a gradient of 10 to 90% B in A over 25 min at1.5 mL/min was performed for full analytical HPLC. HPLC-MS analysis wasperformed on an Agilent 1100 series LC/MSD, using automated Agilent HPLCsystems, with a gradient of 10 to 90% B in A over 10 min on PhenomenexLuna C₈, 5□, 300 Å, 50×2.0 mm at 0.6 mL/min. Semi-preparative HPLCpurification was performed on Phenomenex Jupiter C₄, 5□, 300 Å, 250×10mm, using a gradient of 10 to 90% B in A over 25 min at 4 mL/min onautomated Agilent systems with 215 and/or 254 nm UV detection. Flashcolumn purification was performed on silica gel 60 (Merck 9385) or usingisolute SPE flash silica columns (Biotage, Hengoed, UK).

Preparation of Benzyl (S)-2-((S)-2,5-dihydrofuran-2-yl)-2-hydroxyethylCarbamate (17) (i) Preparation of(3R,3aS,6R,6aS)-Hexahydrofuro[3,2-b]furan-3,6-diylbis(4-methylbenzenesulfonate) (39)

Isomannide (40) (50 g, 342.5 mmol) and p-toluenesulphonyl chloride(143.6 g, 753.2 mmol) were dissolved in a mixture of carbontetrachloride (300 mL), dichloromethane (30 mL) and water (250 mL). Theflask was cooled to 0° C. and a solution of potassium hydroxide (42.0 g,750.0 mmol) in water (42 mL) added dropwise over 2 hours with stirringunder argon. The resulting biphasic mixture was stirred vigorously at 0°C. for 24 hours. The resulting off-white precipitate, comprising amixture of mono- and bistosylates (approximately 1:1), was collected byfiltration in vacuo. The filter cake was washed with water thentriturated with methanol (500 mL). The solid was isolated by filtrationin vacuo to obtain ditosylate (39) as an off-white powder (75 g, 48%).[□]_(D) ¹⁸+96.7° (c=10.5, CHCl₃).

(ii) Preparation of(3R,3aS,6S,6aS)-6-Bromohexahydrofuro[3,2-b]furan-3-yl4-methylbenzenesulfonate (46)

A stirred mixture of ditosylate (39) (16.9 g, 37.22 mmol) and lithiumbromide (4.85 g, 55.84 mmol) in N,N-dimethylformamide (100 mL) washeated at 100° C. for 27 hours. The mixture was allowed to cool thenwater (150 mL) added before extracting with tert-butyl methyl ether(1×100 mL then 5×50 mL). The organic phase was dried (MgSO₄), filteredand reduced in vacuo to give a colourless oil which solidified onstanding. Flash chromatography over silica, eluting with ethylacetate:heptane mixtures 0:100 to 80:20 gave bromotosylate (46) as awhite solid (2.86 g, 29%). TLC (R_(f)=0.45 diethyl ether heptane, 1:1),analytical HPLC: R_(f)=16.768 min; HPLC-MS: 363.1/365.0 [M+H]⁺,380.1/382.1, 749.0/751.0 [2M+Na]⁺; [□]_(D) ¹⁸+64.7° (c=8.5, CHCl₃);δ_(H) (500 MHz, CDCl₃) 2.45 (3H, s, CH₃), 3.74 (1H, dd, 7.05 Hz, CH₂),3.95 (1H, dd, 6.47 Hz, CH₂), 4.14-4.22 (2H, m, CH₂), 4.29 (1H, d, J=3.03Hz, CHBr), 4.68 (1H, d, J=4.03 Hz, CHCH), 4.76 (1H, t, J=4.48 Hz,CHOTs), 4.87 (1H, m, CHCH), 7.36 (2H, brd, J=7.97 Hz, aromatic CH₃CCH),7.83 (2H, brd, J=8.33 Hz, aromatic OSO₂CCH). δ_(C) (125 MHz, CDCl₃)21.69 (CH₃), 50.06 (CHBr), 70.26 (CH₂CHOTs), 76.54 (CH₂CHBr), 78.27(CHOTs), 80.17 and 88.80 (CHCHCHOTs), 127.98 and 129.94 (aromatic CH),133.01 (CHOSO₂C quaternary), 145.28 (CH₃C quaternary).

(iii) Preparation of(3R,3aS,6R,6aR)-6-Hydroxyhexahydrofuro[3,2-b]furan-3-yl4-methylbenzenesulfonate (50)

Isomannide (40) (10 g, 68.49 mmol) and p-toluenesulphonyl chloride (6.53g, 34.25 mmol) were dissolved in a mixture of carbon tetrachloride (50mL), dichloromethane (5 mL) and water (40 mL). The flask was cooled to0° C. and a solution of potassium hydroxide (1.92 g, 34.25 mmol) inwater (5 mL) added dropwise over 30 minutes with stirring. The resultingbiphasic mixture was stirred at 0° C. for 7 hours. Then off-whiteprecipitate was collected by filtration in vacuo then partitionedbetween dichloromethane (30 mL) and water (10 mL). The organic phase waswashed with brine (2×10 mL) then dried (Na₂SO₄), filtered and reduced invacuo to leave a colourless solid. Recrystallisation from carbontetrachloride gave monotosylate (50) as colourless granules (3.92 g,38%). TLC (R_(f)=0.11, EtOAc:heptane 1:1); analytical HPLC main peak,R_(t)=10.692 min; HPLC-MS 318.2, 323.1 [M+Na]⁺, 623.2 [2M+Na]⁺; [□]_(D)¹⁸+72.2° (c=5.4, CHCl₃); δ_(H) (500 MHz, CDCl₃) 2.44 (3H, s, CH₃), 3.54(1H, dd, 7.23 Hz, OCH₂CHOH), 3.78 (1H, dd, 7.59 Hz, OCH₂CHOTs), 3.95(1H, dd, 6.45 Hz, OCH₂CHOH), 4.01 (1H, dd, J=9.33 and 6.64 Hz,OCH₂CHOTs), 4.26 (1H, m, CHOH), 4.42 and 4.48 (each 1H, brt, J=5.03 and5.00 Hz respectively, CHCHCHOH and CHCHCHOTs), 4.90 (1H, dd, 6.84 Hz,CHOTs), 7.37 (2H, d, J=8.13 Hz, aromatic CH₃CCH), 7.82 (2H, d, J=8.20Hz, aromatic OSO₂CCH); δ_(C) (125 MHz, CDCl₃) 21.69 (CH₃), 70.03(CH₂CHOTs), 72.29 (CHOTs), 74.02 (CH₂CHOH), 80.00 (CH₂CHOH), 81.36(CHCHOTs), 81.76 (CHCHOH), 128.00 and 129.89 (aromatic CH), 133.04(CHOSO₂C quaternary), 145.26 (CH₃C quaternary).

(iv) Alternative preparation of(3R,3aS,6R,6aR)-6-Hydroxyhexahydrofuro[3,2-b]furan-3-yl4-methylbenzenesulfonate (50)

A solution of p-toluenesulfonyl chloride (24.8 g, 130 mmol) in pyridine(150 mL) was added to a stirred solution of isomannide (40) (19.0 g, 130mmol) in pyridine (150 mL) over 1 hour at 0° C. then stirred at ambienttemperature for 1 hour. The mixture was poured onto iced-water (1 L)then extracted with dichloromethane (3×300 mL). The organic phase washedwith brine (300 mL), dried (MgSO₄), filtered and reduced in vacuo toleave a residue. Flash chromatography over silica, eluting with ethylacetate:heptane mixtures 0:100 to 50:50 gave monotosylate (50) (23.4 g,60%) as a white solid.

(v) Alternative Preparation of(3R,3aS,6S,6aS)-6-Bromohexahydrofuro[3,2-b]furan-3-yl4-methylbenzenesulfonate (46)

A solution of carbon tetrabromide (18.12 g, 54.63 mmol) in pyridine (100mL) was added to a solution of monotosylate (50) (14.9 g, 49.66 mmol)and triphenylphosphine (26.1 g, 99.32 mmol) in pyridine (150 mL) over 30minutes, then the mixture heated at 65° C. for 1.5 hours under anatmosphere of argon. Water (200 mL) was added then the aqueous phaseextracted with dichloromethane (5×100 mL). The organic phase was washedwith brine (50 mL), then dried (MgSO₄), filtered and reduced in vacuo toleave a residue which was azeotroped with toluene (5×50 mL). Flashchromatography over silica, eluting with diethyl ether:heptane mixtures0:100 to 100:0 gave bromotosylate (46) (7.70 g, 43%) as a white solid.[□]_(D) ¹⁷+68.6° (c=0.51, CHCl₃).

(vi) Preparation of (R)-1-((S)-2,5-Dihydrofuran-2-yl)-2-hydroxyethyl4-methyl Benzenesulfonate (13)

A solution of ammonium chloride (100 mg, 1.87 mmol) in water (1.25 mL)then zinc dust (100 mg, 1.54 mmol) were added to a solution ofbromotosylate (46) (0.5 g, 1.38 mmol) in tetrahydrofuran (5 mL) andpropan-2-ol (2.5 mL) under argon. The mixture was stirred for 16 hoursbefore filtering the suspension through celite in vacuo. The filter cakewas washed with diethyl ether (20 mL). Hydrochloric acid (1M, 20 mL) wasadded to the filtrate then the organic phase separated. The aqueouslayer was extracted with diethyl ether (20 mL) then the combined organicphase was washed with brine (20 mL), then dried (MgSO₄), filtered andreduced in vacuo to leave a residue. Flash chromatography over silica,eluting with ethyl acetate:heptane mixtures 20:80 to 50:50 gave alcohol(13) (292 mg, 75%) as a white solid. [□]_(D) ¹⁵−64.8° (c=9.8, CHCl₃).

(vii) Preparation of Benzyl(S)-2-((S)-2,5-dihydrofuran-2-yl)-2-hydroxyethylcarbamate (17); Zinc and‘One-Pot’ Procedure

A solution of ammonium chloride (560 mg, 10.5 mmol) in water (7 mL) wasadded to a solution of bromotosylate (46) (2.86 g, 7.88 mmol) inpropan-2-ol (14 mL) under argon. Zinc dust (560 mg, 8.67 mmol) was thenadded in portions over 4 minutes then the suspension stirred for 16hours before filtering through celite in vacuo. The filter cake waswashed with diethyl ether (60 mL). Hydrochloric acid (1M, 60 mL) wasadded to the filtrate then the organic phase separated. The aqueouslayer was extracted with diethyl ether (60 mL) then the combined organicphase was washed with brine (60 mL), then dried (MgSO₄), filtered andreduced in vacuo. The residue was dissolved in ammonium hydroxide (18mL) and a solution of ammonia in propan-2-ol (12 mL, 2.0M, 24 mmol) thendivided into three equal portions and heated in sealed tubes at 75° C.for 16 hours. The mixtures were combined using methanol then thesolvents were removed in vacuo. The residue was azeotroped with diethylether (3×10 mL) to obtain(S)-2-amino-1-((S)-2,5-dihydrofuran-2-yl)ethanol which was used withoutfurther purification.

A solution of sodium carbonate (1.75 g, 16.6 mmol) in water (16 mL) wasadded whilst stirring to a solution of(S)-2-amino-1-((S)-2,5-dihydrofuran-2-yl)ethanol (assumed to be 7.88mmol) in 1,4-dioxane (20 mL). The mixture was cooled to 0° C. thenbenzylchloroformate (1.69 mL, 11.82 mmol) was added dropwise over 10minutes. The mixture was stirred at 0° C. for 85 minutes, thendichloromethane (75 mL) and water (100 mL) added. The organic phase wasseparated and the aqueous extracted with dichloromethane (2×50 mL). Theorganic layer was washed with brine (50 mL), then dried (Na₂SO₄),filtered and reduced in vacuo to leave a residue (3.1 g). Flashchromatography over silica, eluting with ethyl acetate:heptane mixtures20:80 to 70:30 gave alcohol (17) (1.10 g, 53%). [□]_(D) ¹⁸−83.1° (c=9.9,CHCl₃).

Preparation of Benzyl (R)-2-((S)-2,5-dihydrofuran-2-yl)-2-hydroxyethylCarbamate (18) (i) Preparation of (3R,3aS,6S,6as)-Hexahydrofuro[3,2-b]furan-3,6-diyl bis(4-methylbenzenesulfonate)(42)

A stirred solution of p-toluenesulfonyl chloride (57.4 g, 301 mmol) andisosorbide (43) (20 g, 137 mmol) in pyridine (315 mL) was heated at 95°C. for 4.5 hours under an atmosphere of argon then stood at ambienttemperature for 16 hours before being poured onto iced-water (1 L). Theaqueous was extracted with dichloromethane (2×500 mL), then the combinedorganic layers were washed with water (2×500 mL), then dried (Na₂SO₄),filtered then reduced in vacuo to leave a viscous oil (65.22 g). The oilwas crystallized from hot methanol (350 mL). The white solid wascollected by filtration in vacuo, then washed with methanol (100 mL) anddried in vacuo to obtain ditosylate (42) as a white solid (45.87 g,74%). TLC (R_(f)=0.30, EtOAc:heptane 2:3), analytical HPLC single mainpeak, R_(t)=20.219 min., HPLC-MS 455.1 [M+H]⁺, 931.2 [2M+Na]⁺, [□]_(D)²⁰+^(57.2)° (c=10.2, CHCl₃); δ_(H) (500 MHz, CDCl₃) 2.44 (6H, s, CH₃),3.68 (1H, dd, 6.46 Hz, CH₂), 3.82-3.87 (2H, m, CH₂), 3.94 (1H, d,J=11.28 Hz, CH₂), 4.46 (1H, d, J=4.44 Hz, CHCHOTs), 4.58 (1H, t, J=4.74Hz, CHCHOTs), 4.82-4.86 (2H, m, CHOTs), 7.32-7.36 (4H, m, aromaticCH₃CCH), 7.74-7.80 (4H, m, aromatic OSO₂CCH).

(ii) Alternative Preparation of(3R,3aS,6S,6aS)-Hexahydrofuro[3,2-b]furan-3,6-diylbis(4-methylbenzenesulfonate) (42)

Triethylamine (123.2 mL, 876 mmol) was added dropwise to a stirredsolution of p-toluenesulfonyl chloride (156.6 g, 822 mmol) andisosorbide (43) (40 g, 274 mmol) in dichloromethane (600 mL) over 15minutes. The mixture was stirred at 25° C. for 16 hours then at 50° C.for 4 hours before diluting with dichloromethane (1 L). The organiclayer was washed with water (2×1 L), then dried (Na₂SO₄), filtered thenreduced in vacuo to leave a viscous oil. The oil was crystallized fromhot methanol (600 mL) to obtain ditosylate (42) as a white solid (120.1g, 97%). [□]_(D) ¹⁵+56.3° (c=11.2, CHCl₃).

(iii) Preparation of(3S,3aS,6S,6aS)-6-Bromohexahydrofuro[3,2-b]furan-3-yl4-methylbenzenesulfonate (47)

Lithium bromide (9.6 g, 110.1 mmol) was added to a stirred solution ofditosylate (42) (20.0 g, 44.05 mmol) in dimethylformamide (100 mL) underan atmosphere of argon. The mixture was heated at 110° C. for 5 hoursthen stood at ambient temperature for 3 days, then heated at 90° C. for3.5 hours. The mixture was diluted with water (250 mL) extracted withtert-butyl methyl ether (4×125 mL) then the organic phase washed withwater (3×125 mL), brine (125 mL), dried (MgSO₄), filtered and reduced invacuo to leave a brown oil (16.8 g). Flash chromatography over silica,eluting with ethyl acetate:heptane mixtures 0:100 to 30:70 gavebromotosylate (47) (11.88 g, 74%) as a pale yellow solid. TLC(R_(f)=0.20, EtOAc:heptane 1:3); analytical HPLC main peak, R_(t)=18.050min; HPLC-MS 381.0/383.0 [M+H₂O+H]⁺, 385.0/387.0 [M+Na]⁺; [□]_(D)¹⁸+51.0° (c=5.0, CHCl₃); δ_(H) (500 MHz, CDCl₃) 2.45 (3H, s, CH₃), 3.84(1H, dd, 3.51 Hz, CH₂), 4.05-4.15 (3H, m, CH₂), 4.28 (1H, d, J=3.40 Hz,CHBr), 4.78 (1H, d, J=3.37 Hz, CHCH), 4.84 (1H, d, J=3.42 Hz, CHOTs),4.90 (1H, d, J=3.37 Hz, CHCH), 7.36 (2H, brd, J=7.98 Hz, aromaticCH₃CCH), 7.79 (2H, brd, J=8.32 Hz, aromatic OSO₂CCH).

(iv) Alternative Preparation of(3S,3aS,6S,6aS)-6-Bromohexahydrofuro[3,2-b]furan-3-yl4-methylbenzenesulfonate (47)

Lithium bromide (19.2 g, 220.2 mmol) was added to a stirred solution ofditosylate (42) (40.0 g, 88.1 mmol) in dimethyl sulfoxide (200 mL) underan atmosphere of argon. The mixture was heated at 110° C. for 8 hoursthen at 120° C. for 1.75 hours. The mixture was diluted with water (500mL) then extracted with tert-butyl methyl ether (4×250 mL). The organicphase was washed with water (3×250 mL) then brine (250 mL), dried(MgSO₄), filtered and reduced in vacuo to leave an orange solid.Recrystallisation from methanol (100 mL) gave bromotosylate (47) (17.47g, 55%) as a pale yellow solid. [□]_(D) ¹⁵+49.5° (c=11.7, CHCl₃).

(v) Preparation of (S)-1-((S)-2,5-Dihydrofuran-2-yl)-2-hydroxyethyl4-methyl Benzenesulfonate (14)

Ammonium chloride (20 mg, 0.37 mmol) then zinc dust (20 mg, 0.31 mmol)were added to a solution of bromotosylate (47) (100 mg, 0.28 mmol) inethanol (1.5 mL) under argon. The mixture was stirred for 16 hoursbefore filtering the suspension through celite in vacuo. The filter cakewas washed with ethanol (20 mL) then the filtrate reduced in vacuo toleave a residue (111 mg). Flash chromatography over silica, eluting withethyl acetate heptane mixtures 20:80 to 40:60 gave alcohol (14) (53 mg,68%) as a white solid. TLC (R_(f)=0.15, EtOAc:heptane 1:2); analyticalHPLC main peak, R_(t)=12.543 min; HPLC-MS 285.1 [M+H]⁺, 302.1, 591.2[2M+Na]⁺; [□]_(D) ¹⁵−86.8° (c=5.3, CHCl₃); δ_(H) (500 MHz, CDCl₃) 2.12(1H, brs, OH), 2.44 (3H, s, aryl-CH₃), 3.77 (2H, d, J=4.85 Hz, CH₂OH),4.54-4.58 (3H, m, CH₂OCH), 4.94-4.98 (1H, m, CHOTs), 5.64-5.67 and5.97-6.00 (2H total, m, CH₂CH═CH), 7.33 (2H, brd, J=8.23 Hz, aromaticCH₃CCH), 7.79 (2H, brd, J=8.31 Hz, aromatic OSO₂CCH); δ_(C) (125 MHz,CDCl₃) 21.660 (CH₃), 62.303 (CH₂OH), 75.940 (OCH₂CH═CH), 82.720 and85.221 (OCHCHOTs), 124.792, 127.977, 129.479 and 129.749 (OCH₂CH═CH andaromatic CH), 133.496 (CHOSO₂C quaternary), 144.973 (CH₃C quaternary).

(vi) Alternative Preparation of(S)-1-((S)-2,5-Dihydrofuran-2-yl)-2-hydroxyethyl 4-methylBenzenesulfonate (14)

A solution of ammonium chloride (200 mg, 3.7 mmol) in water (2.5 mL)then zinc dust (200 mg, 3.1 mmol) were added to a solution ofbromotosylate (47) (1 g, 2.75 mmol) in tetrahydrofuran (10 mL) andpropan-2-ol (5 mL) under argon. The mixture was stirred for 16 hoursbefore filtering the suspension through celite in vacuo. The filter cakewas washed with diethyl ether (20 mL). Hydrochloric acid (1M, 20 mL) wasadded to the filtrate then the organic phase separated. The aqueouslayer was extracted with diethyl ether (20 mL) then the combined organicphase was washed with brine (20 mL), then dried (MgSO₄), filtered andreduced in vacuo to leave a residue (1.06 g). Flash chromatography oversilica, eluting with ethyl acetate:heptane mixtures 20:80 to 50:50 gavealcohol (14) (528 mg, 68%) as a white solid. [□]_(D) ¹⁶−82.7° (c=11.3,CHCl₃).

(vii) Preparation of Benzyl(R)-2-((S)-2,5-dihydrofuran-2-yl)-2-hydroxyethylcarbamate (18). Zinc and‘One-Pot’ Procedure

A solution of ammonium chloride (600 mg, 11.2 mmol) in water (7.5 mL)was added to a solution of bromotosylate (47) (3.0 g, 8.26 mmol) inpropan-2-ol (15 mL) under argon. Zinc dust (600 mg, 9.2 mmol) was thenadded in portions over 4 minutes and the mixture was stirred for 16hours before filtering the suspension through celite in vacuo. Thefilter cake was washed with diethyl ether (60 mL). Hydrochloric acid(1M, 60 mL) was added to the filtrate then the organic phase separated.The aqueous layer was extracted with diethyl ether (60 mL) then thecombined organic phase was washed with brine (60 mL), then dried(MgSO₄), filtered and reduced in vacuo. The residue was dissolved inammonium hydroxide (18 mL) and a solution of ammonia in propan-2-ol (12mL, 2.0M, 24 mmol), then divided into two equal portions and heated insealed tubes at 75° C. for 16 hours. The mixtures were combined usingmethanol then the solvents were removed in vacuo. The residue wasazeotroped with diethyl ether (3×10 mL) to obtain(R)-2-amino-1-((S)-2,5-dihydrofuran-2-yl)ethanol which was used withoutfurther purification.

A solution of sodium carbonate (1.84 g, 17.4 mmol) in water (16 mL) wasadded whilst stirring to a suspension of(R)-2-amino-1-((S)-2,5-dihydrofuran-2-yl)ethanol (assumed to be 8.26mmol) in 1,4-dioxane (20 mL). The mixture was cooled to 0° C. thenbenzylchloroformate (1.77 mL, 12.4 mmol) was added dropwise over 5minutes. The mixture was stirred at 0° C. for 55 minutes thendichloromethane (75 mL) and water (100 mL) added. The organic phase wasseparated and the aqueous extracted with dichloromethane (2×50 mL). Theorganic phase was washed with brine (50 mL), then dried (Na₂SO₄),filtered and reduced in vacuo to leave a residue (3.7 g). Flashchromatography over silica, eluting with ethyl acetate:heptane mixtures20:80 to 70:30 gave alcohol (18) (1.26 g, 58%). [□]_(D) ¹⁶−62.0° (c=5.0,CHCl₃).

Preparation of(S)-2-(Benzyloxycarbonylamino)-1-((S)-2,5-dihydrofuran-2-yl)ethyl4-methylbenzenesulfonate (32)

A solution of p-toluenesulfonyl chloride (252 mg, 1.32 mmol) in pyridine(7.0 mL), alcohol (17) (290 mg, 1.10 mmol) was stirred at 24° C. for 2days then diluted with water (15 mL). The product was extracted intotert-butyl methyl ether (3×20 mL) then dried (MgSO₄), filtered andreduced in vacuo. Flash chromatography over silica, eluting with ethylacetate:heptane mixtures 7:93 to 20:80 gave tosylate (32) (282 mg, 61%)as a colourless oil. TLC (R_(f)=0.35, EtOAc:heptane 1:1), analyticalHPLC single main peak, R_(t)=19.02 min., HPLC-MS 418.2 [M+H]⁺, 857.3[2M+Na]⁺; [□]_(D) ¹¹−86.1° (c=1.103, CHCl₃; δ_(H) (500 MHz, CDCl₃) 2.37(3H, s, aryl-CH₃), 3.29-3.37 and 3.50-3.56 (2H total, m, CH₂NH),4.53-4.56 (2H total, m, OCH₂CH═CH), 4.62-4.66 (1H, m, OCHCH═CH),4.85-4.90 (1H, m, CHOTs), 5.02-5.08 (2H, m, OCH₂Ph), 5.02 (1H, brs, NH),5.65-5.70 and 5.94-5.98 (2H total, m, CH₂CH═CH), 7.27 (2H, d, J=8.12 Hz,aromatic CH₃CCH), 7.29-7.37 (5H, m, phenyl CH), 7.76 (2H, d, J=8.23 Hz,aromatic OSO₂CCH); δ_(C) (125 MHz, CDCl₃) 21.609 (aryl-CH₃), 41.749(CH₂NHCbz), 66.833 (CH₂Ph), 75.939 (OCH₂CH═CH), 81.235 (CHOTs), 85.203(OCHCH═CH), 124.702, 127.887, 128.026, 128.128, 128.504, 129.687 and129.757 (OCH₂CH═CH and aromatic CH), 133.591 (CHOSO₂C quaternary),136.368 (Cbz quaternary), 144.906 (CH₃C quaternary), 156.271 (Cbz C═O).

Alternative Preparation of(S)-2-(Benzyloxycarbonylamino)-1-((S)-2,5-dihydro furan-2-yl)ethyl4-methylbenzenesulfonate (32)

A solution of p-toluenesulfonyl chloride (760 mg, 3.99 mmol) in pyridine(10.0 mL), alcohol (17) (600 mg, 2.28 mmol) was stirred at 40° C. for atotal of 6 hours and stood at 24° C. for 16 hours then diluted withwater (20 mL). The product was extracted into tert-butyl methyl ether(2×50 mL) then dried (MgSO₄), filtered and reduced in vacuo. Flashchromatography over silica, eluting with ethyl acetate:heptane mixtures10:90 to 30:70 gave tosylate (32) (789 mg, 83%) as a white solid.

Preparation of(R)-2-(Benzyloxycarbonylamino)-1-((S)-2,5-dihydrofuran-2-yl) ethyl4-methyl Benzenesulfonate (32b)

A solution of p-toluenesulfonyl chloride (368 mg, 2.03 mmol) in pyridine(1.5 mL) was added to alcohol (18) (333 mg, 1.27 mmol). The mixture wasstirred at 14° C. for 16 hours and at 24° C. for 3.5 hours then dilutedwith tert-butyl methyl ether (35 mL). The organic layer was washed withwater (15 mL), brine (15 mL), then dried (MgSO₄), filtered and reducedin vacuo to leave a pale yellow oil (0.712 g). Flash chromatography oversilica, eluting with ethyl acetate:heptane mixtures 15:85 to 30:70 gavetosylate (32b) (429 mg, 81%) as a white solid. TLC (R_(f)=0.75,EtOAc:heptane 3:1), analytical HPLC single main peak, R_(t)=18.93 min.,HPLC-MS 374.2, 418.2 [M+H]⁺, 857.3 [2M+Na]⁺; [□]_(D) ^(18.5)−30.2°(c=1.326, CHCl₃); δ_(H) (500 MHz, CDCl₃) 2.39 (3H, s, aryl-CH₃),3.29-3.37 and 3.53-3.62 (2H total, m, CH₂NH), 4.44-4.50 and 4.52-4.57(2H total, m, OCH₂CH═CH), 4.59-4.65 (1H, m, OCHCH═CH), 4.87-4.92 (1H, m,CHOTs), 5.05 (2H, m, OCH₂Ph), 5.03 (1H, brs, NH), 5.69-5.73 and5.94-5.98 (2H total, m, CH₂CH═CH), 7.28 (2H, d, J=8.10 Hz, aromaticCH₃CCH), 7.29-7.37 (5H, phenyl CH), 7.77 (2H, d, J=8.10 Hz, aromaticOSO₂CCH); δ_(C) (125 MHz, CDCl₃) 21.627 (aryl-CH₃), 41.119 (CH₂NHCbz),66.856 (CH₂Ph), 75.987 (OCH₂CH═CH), 82.352 (CHOTs), 85.622 (OCHCH═CH),124.792, 127.825, 128.027, 128.126, 128.504, 129.357 and 129.537(OCH₂CH═CH and aromatic CH), 133.674 (CHOSO₂C quaternary), 136.348 (Cbzquaternary), 144.941 (CH₃C quaternary), 156.273 (Cbz C═O).

Epoxidation Studies with(R)-2-(Benzyloxycarbonylamino)-1-((S)-2,5-dihydro furan-2-yl)ethyl4-methylbenzenesulfonate (32b)

(a) 3-Chloroperbenzoic acid (97 mg, ≦77%, 0.43 mmol) was added to astirred solution of alkene (32b) (36 mg, 0.086 mmol) in dichloromethane(1.5 mL). The mixture was stirred for 20 hours at ambient temperaturethen 3-chloroperbenzoic acid (97 mg, ≦77%, 0.43 mmol) was added andstirring continued for 1 day at 24° C. then diluted with dichloromethane(15 mL). The organic phase was washed with aqueous sodium hydroxidesolution (5%, 10 mL), water (10 mL), then dried (Na₂SO₄), filtered andreduced in vacuo to leave a residue (0.038 mg). Flash chromatographyover silica, eluting with ethyl acetate:heptane mixtures 10:90 to 50:50gave (in order of elution) anti-(33b) (16 mg, 43%) as a colourlessviscous oil and syn-epoxide (9 mg, 24%) as a white solid. Data foranti-(33b); TLC (R_(f)=0.50, EtOAc:heptane 1:1), analytical HPLC singlemain peak, R_(t)=17.999 min., HPLC-MS 434.1 [M+H]⁺, 456.1 [M+Na]⁺, 889.2[2M+Na]⁺; [□]_(D) ¹⁷+25.6° (c=2.54, CHCl₃); δ_(H) (500 MHz, CDCl₃) 2.41(3H, s, aryl-CH₃), 3.31-3.38 and 3.60-3.66 (2H total, m, CH₂NH), 3.67(1H, d, J=10.46 Hz, OCH₂CH), 3.75 and 3.81 (each 1H, d, 2.75 Hzrespectively, OCH₂CHCH), 3.94 (1H, d, J=10.57 Hz, OCH₂CH), 4.07 (1H, d,J=6.90 Hz, OCHCHOTs), 4.60-4.64 (1H, m, CHOTs), 4.97-5.01 (1H brt, NH),5.08 (2H, brs, CH₂Ph), 7.29-7.37 (7H, aromatic CH₃CCH and phenyl CH),7.78 (2H, d, J=8.18 Hz, aromatic OSO₂CCH); δ_(C) (125 MHz, CDCl₃) 21.665(aryl-CH₃), 42.054 (CH₂NHCbz), 56.175 and 57.048 (OCH₂CHCH), 67.031(CH₂Ph), 67.672 (OCH₂CH), 76.732 (OCHCHOTs), 79.388 (CHOTs), 127.776,128.108, 128.222, 128.544 and 130.043 (aromatic CH), 133.249 (CHOSO₂Cquaternary), 136.192 (Cbz quaternary), 145.487 (CH₃C quaternary),156.224 (Cbz C═O). Data for syn-epoxide; TLC (R_(f)=0.42, EtOAc:heptane1:1), analytical HPLC single main peak, R_(t)=18.009 min., HPLC-MS 434.1[M+H]⁺, 889.2 [2M+Na]⁺; δ_(H) (500 MHz, CDCl₃) 2.40 (3H, s, aryl-CH₃),3.40-3.47 and 3.58-3.63 (2H total, m, CH₂NH), 3.62 and 3.72 (each 1H, dand dd respectively, 3.01, 0.60 Hz respectively, OCH₂CHCH), 3.67 (1H, d,J=10.68 Hz, OCH₂CH), 3.92 (1H, d, J=7.07 Hz, OCHCHOTs), 3.97 (1H, d,J=10.67 Hz, OCH₂CH), 4.65-4.70 (1H, m, CHOTs), 5.00-5.04 (1H brt, NH),5.05 (2H, brs, CH₂Ph), 7.29-7.37 (7H, aromatic CH₃CCH and phenyl CH),7.83 (2H, d, J=8.11 Hz, aromatic OSO₂CCH); δ_(C) (125 MHz, CDCl₃) 21.664(aryl-CH₃), 41.958 (CH₂NHCbz), 55.948 and 56.425 (OCH₂CHCH), 66.823(CH₂Ph), 68.008 (OCH₂CH), 76.498 (OCHCHOTs), 78.395 (CHOTs), 127.986,128.072, 128.110, 128.493 and 129.928 (aromatic CH), 133.189 (CHOSO₂Cquaternary), 136.383 (Cbz quaternary), 145.177 (CH₃C quaternary),156.202 (Cbz C═O).

(b) To a solution of alkene (32b) (262 mg, 0.63 mmol) in acetonitrile (4mL) and aqueous Na₂.EDTA (4 mL, 0.4 mmol solution) at 0° C. was added1,1,1-trifluoroacetone (0.67 mL, 7.54 mmol) via a pre-cooled syringe. Tothis solution was added in portions a mixture of sodium bicarbonate(0.44 g, 5.28 mmol) and OXONE® (1.20 g, 1.95 mmol) over a period of 55minutes. The mixture was stirred for 2.5 hours then diluted with water(25 mL) and the product extracted into dichloromethane (2×25 mL). Thecombined organic layers were washed with brine (12.5 mL) then dried(Na₂SO₄), filtered and reduced in vacuo to leave a residue (310 mg).Flash chromatography over silica, eluting with ethyl acetate:heptanemixtures 15:85 to 50:50 gave anti-(33b) as a viscous white oil (216 mg,79%).

Epoxidation of (S)-2-(Benzyloxycarbonylamino)-1-((S)-2,5-dihydrofuran-2-yl)ethyl 4-methylbenzenesulfonate (32)

(a) To a solution of alkene (32) (765 mg, 1.83 mmol) in acetonitrile (10mL) and aqueous Na₂.EDTA (10 mL, 0.4 mmol solution) at 0° C. was added1,1,1-trifluoroacetone (1.98 mL, 22.0 mmol). To this solution was addedin portions a mixture of sodium bicarbonate (1.29 g, 15.4 mmol) andOXONE® (3.49 g, 5.68 mmol) over a period of 1.5 hours. The mixture wasstirred for 1.5 hours then diluted with water (30 mL) and the productextracted into dichloromethane (3×30 mL). The combined organic layerswere washed with brine (50 mL) then dried (MgSO₄), filtered and reducedin vacuo. Flash chromatography over silica, eluting with ethylacetate:heptane mixtures 10:90 to 30:70 gave (in order of elution)anti-(33) as a white solid (597 mg, 75%) and syn-epoxide (35 mg, 4%) asa white solid. Data for anti-(33); TLC (R_(f)=0.50, EtOAc:heptane 1:1),analytical HPLC single main peak, R_(t)=17.989 min., HPLC-MS 434.2[M+H]⁺, 889.3 [2M+Na]⁺; [□]_(D) ^(11.5)−49.08° (c=1.630, CHCl₃); δ_(H)(500 MHz, CDCl₃) 2.38 (3H, s, aryl-CH₃), 3.30-3.37 and 3.44-3.50 (2H, m,CH₂NH), 3.73 and 2.74 (2H, each d, 2.73 Hz respectively, OCH₂CHCH), 3.81(1H, d, J=10.08 Hz, OCH₂CH), 3.91 (1H, d, J=10.12 Hz, OCH₂CH), 4.13 (1H,d, J=2.04 Hz, OCHCHOTs), 4.83-4.86 (1H, m, CHOTs), 4.89-5.00 (1H brt,J=5.39 Hz, NH), 5.02-5.09 (2H, m, CH₂Ph), 7.28 (2H, d, J=8.10 Hz,aromatic CH₃CCH), 7.31-7.38 (5H, phenyl CH), 7.76 (2H, d, J=8.22 Hz,aromatic OSO₂CCH); δ_(C) (125 MHz, CDCl₃) 21.636 (aryl-CH₃), 42.085(CH₂NHCbz), 56.414 and 57.217 (OCH₂CHCH), 66.977 (CH₂Ph), 68.582(OCH₂CH), 76.846 (OCHCHOTs), 79.979 (CHOTs), 127.668, 128.073, 128.241,128.551 and 130.001 (aromatic CH), 133.489 (CHOSO₂C quaternary), 136.172(Cbz quaternary), 145.322 (CH₃C quaternary), 156.247 (Cbz C═O). Data forsyn-epoxide; TLC (R_(f)=0.45, EtOAc:heptane 1:1), analytical HPLC mainpeak, R_(t)=17.902 min., HPLC-MS 434.2 [M+H]⁺, 889.3 [2M+Na]⁺; [□]_(D)^(12.5)−38.4° (c=2.277, CHCl₃); δ_(H) (500 MHz, CDCl₃) 2.39 (3H, s,aryl-CH₃), 3.49-3.58 and 3.58-3.66 (2H total, m, CH₂NH), 3.62 (1H, d,J=10.27 Hz OCH₂CH), 3.71 (1H, d, J=3.01 Hz, epoxide CH), 3.88 (1H, brd,J=10.62 Hz, OCH₂CH), 3.88 (1H, brs, epoxide CH), 3.97 (1H, d, J=6.11 Hz,OCHCHOTs), 4.69-4.74 (1H, m, CHOTs), 5.02-5.11 (3H, m, NH and CH₂Ph),7.28-7.38 (7H, aromatic CH₃CCH and phenyl CH), 7.80 (2H, brd, J=8.22 Hz,aromatic OSO₂CCH); δ_(C) (125 MHz, CDCl₃) 21.634 (aryl-CH₃), 41.450(CH₂NHCbz), 55.391 and 55.741 (OCH₂CHCH), 66.828 (CH₂Ph), 67.724(OCH₂CH), 76.526 (OCHCHOTs), 79.632 (CHOTs), 127.805, 128.958, 128.102,128.117, 128.504, 128.550, 128.596, 129.742, 130.002 and 130.177(aromatic CH), 133.093 (CHOSO₂C quaternary), 136.330 (Cbz quaternary),144.990 (CH₃C quaternary), 156.344 (Cbz C═O).

Preparation of (3R,3aR,6R,6aS)-tert-Butyl3-hydroxy-6-(tosyloxy)tetrahydro-2H-furo[3,2-b]pyrrole-4(5H)-carboxylate(35b)

Ethanol (1.5 mL) was added dropwise to a mixture of 10% palladium oncharcoal (20 mg) and anti-(33b) (100 mg, 0.25 mmol) under an atmosphereof argon. The argon was replaced by hydrogen then the suspension wasstirred for 4.5 hours before filtering the mixture through celite invacuo. The filter cake was washed with ethanol (10 mL) then the solventsremoved in vacuo from the filtrate. The residue was azeotroped withtoluene (2×3 mL) to obtain(3R,3aR,6R,6aS)-3-hydroxyhexahydro-2H-furo[3,2-b]pyrrol-6-yl4-methylbenzenesulfonate which was used without further purification.

A solution of sodium carbonate (56 mg, 0.275 mmol) in water (0.75 mL)was added whilst stirring to a solution of(3R,3aR,6R,6aS)-3-hydroxyhexahydro-2H-furo[3,2-b]pyrrol-6-yl4-methylbenzenesulfonate in 1,4-dioxane (0.75 mL). A solution ofdi-tert-butyl dicarbonate (60 mg, 0.275 mmol) in 1,4-dioxane (0.5 mL)was added dropwise over 5 minutes then the mixture stirred for 1 hourbefore adding an additional aliquot of di-tert-butyl dicarbonate (40 mg,0.184 mmol) in 1,4-dioxane (0.25 mL) dropwise over 1 minute. The mixturewas stirred for 70 minutes then water (5 mL) was added and the productextracted into dichloromethane (3×5 mL). The organic layer was washedwith brine (5 mL), then dried (Na₂SO₄), filtered and reduced in vacuo toleave a residue (132 mg). Flash chromatography over silica, eluting withethyl acetate:heptane mixtures 15:85 to 45:55 gave bicyclic alcohol(35b) (58.9 mg, 60%) as a white solid. TLC (R_(f)=0.30, EtOAc:heptane1:1), analytical HPLC single main peak, R_(t)=16.54 min., HPLC-MS 344.1[M+2H−^(t)Bu]⁺, 821.3 [2M+Na]⁺; [□]_(D) ^(18.5)−30.3° (c=6.10, CHCl₃);δ_(H) (500 MHz, CDCl₃) mixture of rotamers major:minor 2:1; 1.44 (6H,brs, (CH₃)₃C, major), 1.46 (3H, brs, (CH₃)₃C, minor), 1.98 (0.33H, d,J=4.00 Hz, OH minor), 2.44 (3H, s, aryl-CH₃), 2.69 (0.66H, d, J=2.88 Hz,OH major), 3.08-3.15 (0.33H, m, BocNCH₂ minor), 3.26-3.32 (0.66H, m,BocNCH₂ major), 3.75-3.87 (2H, m, 1×OCH₂CHOH and 1×BocNCH₂), 3.94-4.02(1H, m, OCH₂CHOH), 4.07 (1H, brs, BocNCH), 4.35 (0.33H, brs, OCH₂CHOHminor), 4.41 (0.66H, brs, OCH₂CHOH major), 4.52 (0.66H, t, J=4.75 Hz,TsOCHCH major), 4.65 (0.33H, t, J=3.95 Hz, TsOCHCH minor), 4.72-4.78(1H, m, TsOCHCH), 7.34 (2H, brd, J=7.82 Hz, aromatic CH₃CCH), 7.82 (2H,brd, J=8.01 Hz, aromatic OSO₂CCH); δ_(C) (125 MHz, CDCl₃) 21.681(aryl-CH₃), 28.294/28.386 ((CH₃)₃C), 46.810/48.177 (BocNCH₂),68.153/68.484 (BocNCH), 75.484/75.697 (OCH₂CHOH), 76.228/76.980(OCH₂CHOH), 76.269/76.585 (TsOCHCH), 79.391/80.233 (TsOCHCH),81.079/81.139 ((CH₃)₃C quaternary), 127.973, 129.911, 129.966 and130.125 (aromatic CH), 133.144 (CHOSO₂C quaternary), 145.247 (CH₃Cquaternary), 153.161/154.244 (Boc C═O).

Preparation (3R,3aR,6S,6aS)-tert-Butyl3-hydroxy-6-(tosyloxy)tetrahydro-2H-furo[3,2-b]pyrrole-4(5H)-carboxylate(35)

Ethanol (20 mL) was added dropwise to a mixture of 10% palladium oncharcoal (50 mg) and anti-(33) (578 mg, 1.33 mmol) under an atmosphereof argon. The argon was replaced by hydrogen then the suspension wasstirred for 1.5 hours before filtering the mixture through celite invacuo. The filter cake was washed with ethanol then the solvents removedin vacuo from the filtrate to obtain(3R,3aR,6S,6aS)-3-hydroxyhexahydro-2H-furo[3,2-b]pyrrol-6-yl4-methylbenzenesulfonate which was used without further purification.

A solution of sodium carbonate (297 mg, 2.80 mmol) in water (10 mL) wasadded whilst stirring to a solution of(3R,3aR,6S,6aS-3-hydroxyhexahydro-2H-furo[3,2-b]pyrrol-6-yl4-methylbenzenesulfonate in 1,4-dioxane (7 mL). A solution ofdi-tert-butyl dicarbonate (320 mg, 1.47 mmol) in 1,4-dioxane (3 mL) wasadded then the mixture stirred for 2 hours then stored at 4° C. for 16hours then water (30 mL) was added and the product extracted intodichloromethane (3×30 mL). The organic layer was washed with brine (30mL), then dried (MgSO₄), filtered and reduced in vacuo to leave aresidue. Flash chromatography over silica, eluting with ethylacetate:heptane mixtures 20:80 to 40:60 gave bicyclic alcohol (35) (292mg, 55%) as a white solid. TLC (R_(f)=0.38, EtOAc:heptane 3:2),analytical HPLC single main peak, R_(t)=16.80 min., HPLC-MS 344.1[M+2H−^(t)Bu]⁺, 821.3 [2M+Na]⁺; [□]_(D) ¹⁵−36.5° (c=3.42, CHCl₃); δ_(H)(500 MHz, CDCl₃) mixture of rotamers major:minor 2:1; 1.43 (6H, brs,(CH₃)₃C, major), 1.47 (3H, brs, (CH₃)₃C, minor), 2.19 (0.33H, d, J=4.06Hz, OH minor), 2.80 (0.66H, d, J=3.10 Hz, OH major), 2.45 (3H, s,aryl-CH₃), 3.27 (0.33H, dd, J=13.48 and 3.65 Hz, BocNCH₂ minor), 3.35(0.66H, dd, 3.83 Hz, BocNCH₂ major), 3.72-3.82 (3H, m, 2×OCH₂CHOH and1×BocNCH₂), 4.21-4.24 (1H, brs, BocNCH), 4.37 (0.33H, brs, OCH₂CHOHminor), 4.44 (0.66H, brs, OCH₂CHOH major), 4.46 (0.66H, brd, J=4.62 Hz,TsOCHCH major), 4.64 (0.33H, brd, J=4.18 Hz, TsOCHCH minor), 4.74(0.33H, brd, J=3.09 Hz, TsOCH minor), 4.77 (0.66H, brd, J=3.43 Hz, TsOCHmajor), 7.35 (2H, brd, J=7.95 Hz, aromatic CH₃CCH), 7.78 (2H, brd,J=8.24 Hz, aromatic OSO₂CCH); δ_(C) (125 MHz, CDCl₃) 21.679 (aryl-CH₃),28.308/28.434 ((CH₃)₃C), 50.487/51.186 (BocNCH₂), 68.000/68.553(BocNCH), 74.330/74.458 (OCH₂CHOH), 75.499/76.335 (OCH₂CHOH),80.187/80.914 (TsOCHCH), 80.849 ((CH₃)₃C quaternary), 83.599/84.662(TsOCHCH), 127.816, 127.852 and 130.125 (aromatic CH), 133.081/133.268(CHOSO₂C quaternary), 145.371 (CH₃C quaternary), 153.259/154.119 (BocC═O).

Preparation of (3R,3aR,6S,6aS)— tert-Butyl3-hydroxy-6-(methylsulfonyloxy)tetrahydro-2H-furo[3,2-b]pyrrole-4(5H)-carboxylate(53) (i) Preparation of(S)-2-(Benzyloxycarbonylamino)-1-((S)-2,5-dihydrofuran-2-yl)ethylMethane Sulfonate (51)

Triethylamine (0.594 mL, 4.25 mmol) then methanesulfonyl chloride (0.309mL, 3.99 mmol) were added to a stirred solution of (alcohol (17) (700mg, 2.66 mmol) in dichloromethane (15 mL). The mixture was stirred for 2hours then diluted with water (20 mL). The product was extracted intodichloromethane (2×25 mL) then dried (MgSO₄), filtered and reduced invacuo. Flash chromatography over silica, eluting with ethylacetate:heptane mixtures 10:90 to 40:60 gave mesylate (51) (584 mg, 64%)as a white solid. TLC (R_(f)=0.35, EtOAc:heptane 1:1), analytical HPLCsingle main peak, R_(t)=14.21 min., HPLC-MS 342.1 [M+H]⁺, 364.1 [M+Na]⁺,705.2 [2M+Na]⁺; [□]_(D) ^(12.5)−67.0° (c=1.034, CHCl₃); δ_(H) (500 MHz,CDCl₃) 3.02 (3H, s, OSO2CH₃), 3.48 (1H, dt, 6.40 Hz, CH₂NH), 3.62 (1H,dt, 6.24 Hz, CH₂NH), 4.61-4.71 (3H, m, OCH₂CH═CH and OCHCH═CH),4.93-4.97 (1H, m, CHOMs), 5.10 (2H, brs, OCH₂Ph), 5.26 (1H, brs, NH),5.82-5.87 and 6.06-6.11 (2H total, m, CH₂CH═CH), 7.28-7.37 (5H, m,aromatic CH); δ_(C) (125 MHz, CDCl₃) 38.487 (OSO₂CH₃), 42.063(CH₂NHCbz), 67.002 (CH₂Ph), 75.768 (OCH₂CH═CH), 81.235 (CHOMs), 85.485(OCHCH═CH), 124.835, 128.096, 128.177, 128.519, and 130.104 (OCH₂CH═CHand aromatic CH), 136.275 (Cbz quaternary), 156.500 (Cbz C═O).

(ii) Preparation of(S)-2-(Benzyloxycarbonylamino)-1-((1S,2S,5S)-3,6-dioxabicyclo[3.1.0]hexan-2-yl)ethylmethanesulfonate anti-(52)

To a solution of mesylate (51) (439 mg, 1.29 mmol) in acetonitrile (7mL) and aqueous Na₂.EDTA (7 mL, 0.4 mmol solution) at 0° C. was added1,1,1-trifluoroacetone (1.38 mL, 15.4 mmol). To this solution was addedin portions a mixture of sodium bicarbonate (0.907 g, 10.8 mmol) andOXONE® (2.45 g, 3.99 mmol) over a period of 80 minutes. The mixture wasstirred for 30 minutes then diluted with water (10 mL) and the productextracted into dichloromethane (1×10 mL and 2×20 mL). The combinedorganic layers were washed with brine (30 mL) then dried (MgSO₄),filtered and reduced in vacuo. Flash chromatography over silica, elutingwith ethyl acetate:heptane mixtures 10:90 to 50:50 gave (in order ofelution) anti-(52) (271 mg, 59%) and syn-epoxide (71 mg, 15%) ascolourless oils. Data for anti-(52); TLC (R_(f)=0.41, EtOAc:heptane3:2), analytical HPLC single main peak, R_(t)=13.556 min., HPLC-MS 358.2[M+H]⁺, 380.2 [M+Na]⁺, 737.3 [2M+Na]⁺; [□]_(D) ^(12.5)−28.8° (c=1.910,CHCl₃); δ_(H) (500 MHz, CDCl₃) 2.99 (3H, s, OSO₂CH₃), 3.47 and 3.50 (1Htotal, each brt, J=6.24 Hz, CH₂NH), 3.60 and 3.63 (1H total, each brt,5.63 respectively, CH₂NH), 3.86-3.90 (3H, m, OCH₂CHCH), 3.98 (1H, d,J=10.27 Hz, OCH₂CH), 4.17 (1H, d, J=2.70 Hz, OCHCHOMs), 4.83-4.87 (1H,m, CHOMs), 5.08-5.14 (2H m, CH₂Ph), 5.23 (1H, brs, NH), 7.30-7.36 (5H,m, aromatic CH); δ_(C) (125 MHz, CDCl₃) 38.570 (OSO₂CH₃), 42.217(CH₂NHCbz), 56.231 and 57.062 (OCH₂CHCH), 67.176 (CH₂Ph), 68.353(OCH₂CH), 77.063 (OCHCHOMs), 79.435 (CHOMs), 128.209, 128.343 and128.587 (aromatic CH), 136.089 (Cbz quaternary), 156.528 (Cbz C═O). Datafor syn-epoxide; TLC (R_(f)=0.29, EtOAc:heptane 3:2), analytical HPLCmain peak, R_(t)=13.639 min., HPLC-MS 358.1 [M+H]⁺, 737.2 [2M+Na]⁺;[□]_(D) ^(12.5)−9.2° (c=3.543, CHCl₃); δ_(H) (500 MHz, CDCl₃) 3.04 (3H,s, OSO₂CH₃), 3.60-3.80 (2H, m, CH₂NH), 3.72 (1H, d, J=10.54 Hz,OCH₂CHCH), 3.79 (1H, d, J=2.90 Hz, epoxide CH), 3.96 (1H, d, J=2.84 Hz,epoxide CH), 3.99 (1H, d, J=7.36 Hz, OCHCHOMs) 4.06 (1H, d, J=10.68 Hz,OCH₂CHCH), 4.78 (1H, dt, 4.25 Hz, CHOMs), 5.07-5.14 (2H, m, CH₂Ph), 5.29(1H, brs, NH), 7.29-7.37 (5H, m, aromatic CH); δ_(C) (125 MHz, CDCl₃)38.234 (OSO₂CH₃), 42.241 (CH₂NHCbz), 55.571 and 56.081 (OCH₂CHCH),67.047 (CH₂Ph), 67.852 (OCH₂CH), 76.662 (OCHCHOMs), 80.615 (CHOMs),128.023, 128.195 and 128.531 (aromatic CH), 136.212 (Cbz quaternary),156.653 (Cbz C═O).

(iii) Ethanol (3 mL) was added dropwise to a mixture of 10% palladium oncharcoal (5 mg) and anti-(52) (60 mg, 0.17 mmol) under an atmosphere ofargon. The argon was replaced by hydrogen then the suspension wasstirred for 1 hour before filtering the mixture through celite in vacuo.The filter cake was washed with ethanol then the solvents removed invacuo from the filtrate to obtain(3R,3aR,6S,6aS)-3-hydroxyhexahydro-2H-furo[3,2-b]pyrrol-6-ylmethanesulfonate which was used without further purification.

A solution of sodium carbonate (37 mg, 0.35 mmol) in water (2 mL) wasadded whilst stirring to a solution of(3R,3aR,6S,6aS)-3-hydroxyhexahydro-2H-furo[3,2-b]pyrrol-6-ylmethanesulfonate in 1,4-dioxane (1 mL). A solution of di-tert-butyldicarbonate (40 mg, 0.18 mmol) in 1,4-dioxane (1 mL) was added then themixture stirred for 3 hours before adding di-tert-butyl dicarbonate (40mg, 0.18 mmol). The mixture was stirred for 16 hours then water (10 mL)was added and the product extracted into dichloromethane (1×10 mL and2×15 mL). The organic layer was washed with brine (15 mL), then dried(MgSO₄), filtered and reduced in vacuo to leave a residue. Flashchromatography over silica, eluting with ethyl acetate:heptane mixtures20:80 to 50:50 gave bicyclic alcohol (53) (27 mg, 49%) as a white solid.TLC (R_(f)=0.15, EtOAc:heptane 1:1), HPLC-MS 268.1 [M+2H−^(t)Bu]⁺, 346.1[M+Na]⁺, 669.3 [2M+Na]⁺; [□]_(D) ^(12.5)−46.1° (c=2.820, CHCl₃); δ_(H)(500 MHz, CDCl₃) mixture of rotamers major:minor 2:1; 1.45 (6H, brs,(CH₃)₃C major), 1.49 (3H, brs, (CH₃)₃C minor), 2.20 (1H, brs, OH), 3.05(1H, s, OSO₂CH₃ minor), 3.06 (2H, s, OSO₂CH₃ major), 3.43 (0.33H, dd,2.70 Hz, BocNCH₂ minor), 3.50 (0.66H, dd, 3.75 Hz, BocNCH₂ major),3.82-3.87 (2H, m, 1.33×OCH₂CHOH and 0.66×BocNCH₂ major), 3.90 (0.66H,dd, J=9.46 and 2.77 Hz, OCH₂CHOH major), 3.96 (0.33H, brd, J=13.48 Hz,BocNCH₂ minor), 4.26 (0.33H, d, J=3.92 Hz, BocNCH minor), 4.30 (0.66H,d, J=3.58 Hz, BocNCH major), 4.42 (0.33H, brs, OCH₂CHOH minor), 4.50(0.66H, brs, OCH₂CHOH major), 4.72 (0.66H, d, J=2.87 Hz, MsOCHCH major),4.80 (0.33H, d, J=3.54 Hz, MsOCHCH minor), 5.00 (1H, brs, MSOCH); δ_(C)(125 MHz, CDCl₃) 28.352/28.446 ((CH₃)₃C quaternary), 38.644/38.711(OSO₂CH₃), 50.675/51.401 (BocNCH₂), 68.078/68.631 (BocNCH),74.505/74.590 (OCH₂CHOH), 75.662/76.402 (OCH₂CHOH), 79.776/80.274(MsOCHCH), 81.013/81.181 (C(CH₃)₃ quaternary), 83.872/84.785 (MsOCHCH),153.452/154.266 (Boc C═O).

Preparation of (3aS,6S,6aS)-(9H-fluoren-9-yl)methyl6-tert-butoxy-3-oxotetrahydro-2H-furo[3,2-b]pyrrole-4(5H)-carboxylate(4c)

(i) Preparation of Benzyl(S)-2-tert-butoxy-2-((S)-2,5-dihydrofuran-2-yl)ethylcarbamate (26).Alcohol (17) (270 mg, 1.02 mmol) was dissolved in anhydrousdichloromethane (8 mL) in a 50 mL glass pressure tube and cooled to −78°C. Isobutene (˜3 mL) was condensed into the solution and conc. H₂SO₄ (25□L) added. The tube was sealed and stirred at ambient temperatureovernight. The sealed tube was cooled to −78° C., N-methylmorpholine (60□L, 1 eq. w.r.t. conc. H₂SO₄) added and allowed to warm to ambienttemperature, unsealed, with stirring over 2 h. Dichloromethane (25 mL)was added and the organics washed with pH 3 HCl (25 mL), NaHCO₃ (25 mL)then brine (25 mL) and dried (Na₂SO₄). The solvents were removed invacuo to give a tan oil. The crude oil was purified on a 5 g Flashsilica cartridge eluting with a gradient of heptane:ethyl acetate9:1→6:1. Desired fractions were combined and reduced in vacuo to provideether (26) as a clear gum (222 mg, 68%). TLC (KMnO₄ stain, R_(f)=0.46,heptane:ethyl acetate 1:2), analytical HPLC R_(t)=17.10 min, HPLC-MS(single main UV peak with R_(t)=2.91 min, 264.1 [M+2H−Bu]⁺, 342.2[M+Na]⁺, 661.3 [2M+Na]⁺); [□]_(D) ¹⁸−94.3° (c=1.962, CHCl₃).

(ii) Preparation of epoxide mixture Benzyl(S)-2-((1R,2R,5R)-3,6-dioxabicyclo[3.1.0]hexan-2-yl)-2-tert-butoxyethylcarbamatesyn-(27) and Benzyl(S)-2-((1S,2R,5S)-3,6-dioxabicyclo[3.1.0]hexan-2-yl)-2-tert-butoxyethylcarbamateanti-(28). Method 1; meta-Chloroperbenzoic acid. Ether (26) (210 mg,0.66 mmol) was dissolved in anhydrous dichloromethane (10 mL) withstirring and meta-chloroperoxybenzoic acid (1.48 g, 77% reagent, 6.6mmol) added. The mixture was stirred at ambient temperature under argonfor 16 h. Dichloromethane (20 mL) was added and the organic phase washedwith 10% aqueous w/v solution of sodium hydroxide (2×20 mL), then dried(Na₂SO₄), filtered and reduced in vacuo to leave a clear gum (200 mg).The crude gum was purified on a 5 g Flash silica cartridge eluting witha gradient of heptane:ethyl acetate 9:1→7:1. Desired fractionscontaining the co-eluting epoxides were combined and reduced in vacuo toprovide a viscous oil (183 mg, 82.7%). TLC (R_(f)=0.30 (figure of eightmixture of syn and anti epoxides), EtOAc:heptane 2:1), HPLC-MS 236.1,280.1 [M+2H−Bu]⁺, 358.2 [M+Na]⁺, 693.2 [2M+Na]⁺.

(iii) Alternative preparation of epoxide mixture Benzyl(S)-2-((1R,2R,5R)-3,6-dioxabicyclo[3.1.0]hexan-2-yl)-2-tert-butoxyethylcarbamatesyn-(27). and Benzyl(S)-2-((1S,2R,5S)-3,6-dioxabicyclo[3.1.0]hexan-2-yl)-2-tert-butoxyethylcarbamateanti-(28). Method 2; Oxone. To a solution of ether (26) (9.5 mg, 0.030mmol) in acetonitrile (0.15 mL) and aqueous Na₂.EDTA (0.15 mL, 0.4 mmolsolution) at 0° C. was added 1,1,1-trifluoroacetone (0.032 mL, 0.36mmol). To this solution was added in portions a mixture of sodiumbicarbonate (21 mg, 0.25 mmol) and OXONE® (57 mg, 0.092 mmol) over aperiod of 1 hour. The mixture was stirred for 50 minutes then dilutedwith water (5 mL) and the product extracted into dichloromethane (2×50mL). The combined organic layers were washed with brine (5 mL) thendried (Na₂SO₄), filtered and reduced in vacuo. ¹H nmr analysis of theresidue indicated a 10:1 mixture benzyl anti-(28) and syn-(27)respectively (6.7 mg).

(iv) Preparation of Benzyl(S)-2-((1R,2R,5R)-3,6-dioxabicyclo[3.1.0]hexan-2-yl)-2-tert-butoxyethylcarbamatesyn-(27) and (3R,3aR,6S,6aS)-benzyl6-tert-butoxy-3-hydroxytetrahydro-2H-furo[3,2-b]pyrrole-4(5H)-carboxylate(29). Epoxide mixture (27, 28) (175 mg, 0.52 mmol) was dissolved inanhydrous THF (3 mL), cooled to 0° C. and sodium hydride (60% dispersionin oil) (26.2 mg, 0.65 mmol) added. The mixture was stirred at ambienttemperature for 3 h. Dichloromethane (25 mL) was added and the organicphase washed with brine (1×25 mL), then dried (Na₂SO₄), filtered andreduced in vacuo to leave an opaque gum (˜150 mg). The crude gum waspurified on a 5 g Flash silica cartridge eluting with a gradient ofheptane:ethyl acetate 9:1→5:1 to provide two products:

-   -   (a) Syn-epoxide (27) as a viscous oil (39.2 mg, 0.12 mmol,        22.4%), TLC (R_(f)=0.37, EtOAc:heptane 1:1), analytical HPLC        R_(t)=15.61 min, HPLC-MS 280.1 [M+2H−Bu]⁺, 358.2 [M+Na]⁺, 693.2        [2M+Na]⁺.    -   (b) Bicycle alcohol (29) as a viscous oil (80.4 mg, 0.24 mmol,        46%), TLC (R_(f)=0.31, EtOAc:heptane 1:1), analytical HPLC        R_(t)=15.17 min, HPLC-MS 236.1, 280.1 [M+2H−Bu]⁺, 358.2 [M+Na]⁺,        693.2 [2M+Na]⁺; [□]_(D) ¹⁸−46.0° (c=8.04, CHCl₃); ¹H NMR (500        MHz, CDCl₃ at 300K): δ 1.18 (s, C(CH₃)₃, 9H), 1.98 (d, J=4.0 Hz,        OH, 0.4H), 2.76 (d, J=2.6 Hz, OH, 0.6H), 3.36-3.44 (m, CbzNCH₂,        0.6H), 3.45-3.52 (m, CbzNCH₂, 1H), 3.62 (d, J=11.8 Hz, CbzNCH₂,        0.4H), 3.70-3.92 (m, OCH₂CHOH, 2H), 4.04 (b, CHOBu^(t), 1H),        4.26 (b, NCHCHOH, 1H), 4.36 (b, OCH₂CHOH, 0.4H), 4.45 (d, J=4.6        Hz, Bu^(t)OCHCHO, 1H), 4.48 (b, OCH₂CHOH, 0.6H), 5.09-5.26 (m,        OCH₂Ph, 2H), 7.34-7.37 (bm, 5H aromatic); ¹³C NMR (125 MHz,        CDCl₃ at 300K): δ 28.08/28.12 (C(CH₃)₃), 53.48/53.71 (CbzNCH₂),        67.11/67.29 (OCH₂Ph), 68.31/69.27 (NCHCHOH), 72.51/73.29        (CHOBu^(t)), 73.88 (OCH₂CHOH), 74.72/74.78 (C(CH₃)₃),        75.80/76.62 (OCH₂CHOH), 86.89/87.52 (Bu^(t)OCHCHO),        127.81/127.93/128.06/128.23/128.50/128.68 (aromatic CH), 136.43        (aromatic quaternary), 154.51/155.26 (NHC(O)O).

(v) Preparation of (3R,3aR,6S,6aS)-(9H-fluoren-9-yl)methyl6-tert-butoxy-3-hydroxytetrahydro-2H-furo[3,2-b]pyrrole-4(5H)-carboxylate(4b). Bicycle alcohol (29) (75 mg, 0.22 mmol) was dissolved in methanol(5 mL), cooled to 0° C. and 10% palladium on charcoal (20 mg) added. Themixture was stirred, then evacuated and flushed with hydrogen. Themixture was warmed to ambient temperature and after 1 h. filteredthrough celite. The filter cake was washed with ethanol (3×5 mL) and thecombined filtrates reduced in vacuo to provide the crude amine (˜45 mg).HPLC-MS 146.1 [M+2H−Bu]⁺, 202.1 [M+H]⁺, 425.2 [M+Na]⁺. The crude aminewas dissolved in 1,4-dioxane (3.5 mL) with stirring, ice-cooled and asolution of sodium carbonate (50 mg, 0.47 mmol) in water (3.5 mL) wasadded. 9-Fluorenylmethyl chloroformate (61 mg, 0.234 mmol) in1,4-dioxane (2.5 mL) was added dropwise over 30 minutes and the mixturestirred for a further 1 h. CHCl₃ (25 mL) was then added and the organicphase washed with 0.1N HCl (25 mL), sat. NaHCO₃ (25 mL), then brine (25mL) and dried (Na₂SO₄). The organic layer was filtered and reduced invacuo to leave a clear film (˜100 mg). The crude film was purified on a5 g Flash silica cartridge eluting with a gradient of heptane:ethylacetate 8:1→2:1 to provide alcohol (4b) as a white solid (74.4 mg, 0.175mmol, 78%). TLC (R_(f)=0.33, EtOAc:heptane 1:1), analytical HPLCR_(t)=18.78 min, HPLC-MS 368.1 [M+2H−Bu]⁺, 424.2 [M+H]⁺, 446.2 [M+Na]⁺,869.4 [2M+Na]⁺; [□]_(D) ¹⁸−34.8° (c=6.9, CHCl₃).

(vi) Preparation of (3aS,6S,6aS)-(9H-fluoren-9-yl)methyl6-tert-butoxy-3-oxotetrahydro-2H-furo[3,2-b]pyrrole-4(5H)-carboxylate(4c). Alcohol (4b) (70 mg, 0.165 mmol) was dissolved in anhydrousdichloromethane (5 mL) with stirring under argon. Dess-Martinperiodinane (141 mg, 0.33 mmol) was added and the mixture stirred for 2h. The mixture was diluted with DCM (20 mL) and washed with sat.NaHCO₃/0.25M Na₂S₂O₃, sat. NaHCO₃, brine (25 mL each) and dried(Na₂SO₄). The organic layer was filtered and reduced in vacuo to leave aclear film (˜110 mg). The crude film was purified on a 5 g Flash silicacartridge eluting with a gradient of heptane:ethyl acetate 7:1→2:1 toprovide ketone (4c) as a colourless gum (70.5 mg, 0.165 mmol, 99.8%).TLC (R_(f)=0.50, EtOAc:heptane 1:1), analytical HPLC broad peak withR_(t)=18.58-20.92 min, HPLC-MS 366.1 [M+2H−Bu]⁺, 422.2 [M+H]⁺, 444.2[M+Na]⁺, 865.4 [2M+Na]⁺; [□]_(D) ¹⁸−1000.8° (c=6.5, CHCl₃); ¹H NMR (500MHz, CDCl₃ at 300K): δ 1.22 (s, C(CH₃)₃, 9H), 3.55-3.67 (m, FmocNCH₂,1.6H), 3.78-3.83 (m, FmocNCH₂, 0.4H), 3.90-3.96 (m, OCH₂C(O), 1H),4.10-4.19 (m, OCH₂C(O)+CHOBu^(t), 2H), 4.25-4.42 (m, 0.4+0.6FmocCH+1×FmocCH₂+.NCHC(O), 3H), 4.50 (q, J=6.7, 3.7 Hz, FmocCH₂),4.59/4.64 (b, Bu^(t)OCHCHO, 1H), 7.30 (d, J=6.65 Hz, Fmoc H-2 and H-7),7.39 (t, J=7.5 Hz, Fmoc H-3 and H-6), 7.57 (d, J=7.2 Hz, 1.2 Fmoc H-1and H-8), 7.66 (d, J=7.1 Hz, 0.8 Fmoc H-1 or H-8), 7.76 (d, J=7.55 Hz,Fmoc H-4 and H-5); ¹³C NMR (125 MHz, CDCl₃ at 300K): δ 28.10 (C(CH₃)₃),47.13 (FmocCH), 53.40/53.84 (FmocNCH₂), 61.12/61.56 (NCHC(O)),67.63/68.38 (FmocCH₂), 69.99 (OCH₂C(O)), 72.54/73.21 (CHOBu^(t)),75.05/75.13 (C(CH₃)₃), 86.36/87.37 (Bu^(t)OCHCHO), 119.89/119.96 (FmocC-4 and C-5), 124.97/125.03/125.25/125.59 (Fmoc C-1 and C-8),126.99/127.04 (Fmoc C-2 and C-7), 127.67 (Fmoc C-3 and C-6),141.22/141.33/143.71/143.87/144.47 (Fmoc quaternary aromatics), 155.17(FmOC(O)N), 208.02/208.31 (C═O).

Preparation of (3aS,6R,6aS)-(9H-fluoren-9-yl)methyl6-tert-butoxy-3-oxotetrahydro-2H-furo[3,2-b]pyrrole-4(5H)-carboxylate(3c)

(i) Preparation of Benzyl(R)-2-tert-butoxy-2-((S)-2,5-dihydrofuran-2-yl)ethylcarbamate (26b).Alcohol (18) (400 mg, 1.52 mmol) was dissolved in anhydrousdichloromethane (8 mL) in a 50 mL glass pressure tube and cooled to −78°C. Isobutene (˜4 mL) was condensed into the solution and conc. H₂SO₄ (35□L) added. The tube was sealed and stirred at ambient temperature for 6h. The sealed tube was cooled to −78° C., N-methylmorpholine (75 □L, 1eq. w.r.t. conc. H₂SO₄) added and allowed to warm to ambienttemperature, unsealed, with stirring over 2 h. Dichloromethane (20 mL)was added and the organics washed with pH 3 HCl (25 mL), NaHCO₃ (25 mL)then brine (25 mL) and dried (Na₂SO₄). The solvents were removed invacuo to give an opaque gum (350 mg). The crude gum was purified on a 5g Flash silica cartridge eluting with a gradient of heptane:ethylacetate 7:1→2:1. Desired fractions were combined and reduced in vacuo toprovide ether (26b) as a thick clear oil (204 mg, 42%) and recoveredstarting alcohol (108 mg, 27%). TLC (KMnO₄ stain, R_(f)=0.70,heptane:ethyl acetate 2:1), analytical HPLC R_(t)=16.85 min, HPLC-MS(single main UV peak with R_(t)=2.85 min, 264.1 [M+2H−Bu]⁺, 342.2[M+Na]⁺, 661.3 [2M+Na]⁺); [□]_(D) ¹⁸−560.8° (c=2.068, CHCl₃).

(ii) Preparation of epoxide mixture Benzyl(R)-2-((1R,2R,5R)-3,6-dioxabicyclo[3.1.0]hexan-2-yl)-2-tert-butoxyethylcarbamatesyn-(27b). and Benzyl(R)-2-((1S,2R,5S)-3,6-dioxabicyclo[3.1.0]hexan-2-yl)-2-tert-butoxyethylcarbamateanti-(28b). Method 1; meta-Chloroperbenzoic acid. Ether (26b) (175 mg,0.55 mmol) was dissolved in anhydrous dichloromethane (7.5 mL) withstirring and meta-chloroperoxybenzoic acid (1.22 g, 77% reagent, 5.5mmol) added. The mixture was stirred at ambient temperature under argonfor 16 h. Dichloromethane (20 mL) was added and the organic phase washedwith 10% aqueous w/v solution of sodium hydroxide (2×50 mL), then dried(Na₂SO₄), filtered and reduced in vacuo to leave a clear oil (180 mg).The crude oil was purified on a 5 g Flash silica cartridge eluting witha gradient of heptane:ethyl acetate 8:1→2:1. Desired fractionscontaining the co-eluting epoxides were combined and reduced in vacuo toprovide a clear gum (171 mg, 92.7%). TLC (R_(f)=0.28 (mixture of syn andanti epoxides), EtOAc:heptane 1:2), HPLC-MS 236.1, 280.1 [M+2H−Bu]⁺,358.2 [M+Na]⁺, 693.2 [2M+Na]⁺.

(iii) Alternative preparation of epoxide mixture Benzyl(R)-2-((1R,2R,5R)-3,6-dioxabicyclo[3.1.0]hexan-2-yl)-2-tert-butoxyethylcarbamatesyn-(27b). and Benzyl(R)-2-((1S,2R,5S)-3,6-dioxabicyclo[3.1.0]hexan-2-yl)-2-tert-butoxyethylcarbamateanti-(28b). Method 2; Oxone. To a solution of ether (26b) (9.5 mg, 0.030mmol) in acetonitrile (0.15 mL) and aqueous Na₂.EDTA (0.15 mL, 0.4 mmolsolution) at 0° C. was added 1,1,1-trifluoroacetone (0.032 mL, 0.36mmol). To this solution was added in portions a mixture of sodiumbicarbonate (21 mg, 0.25 mmol) and OXONE® (57 mg, 0.092 mmol) over aperiod of 1 hour. The mixture was stirred for 50 minutes then dilutedwith water (5 mL) and the product extracted into dichloromethane (2×50mL). The combined organic layers were washed with brine (5 mL) thendried (Na₂SO₄), filtered and reduced in vacuo. ¹H nmr analysis of theresidue indicated a 10:1 mixture of anti-(28b) and syn-(27b)respectively (8.9 mg).

(iv) Preparation of Benzyl(R)-2-((1R,2R,5R)-3,6-dioxabicyclo[3.1.0]hexan-2-yl)-2-tert-butoxyethylcarbamatesyn-(27b) and (3R,3aR,6R,6aS)-benzyl6-tert-butoxy-3-hydroxytetrahydro-2H-furo[3,2-b]pyrrole-4(5H)-carboxylate(29b). Epoxide mixture (27b, 28b) (165 mg, 0.49 mmol) was dissolved inanhydrous THF (3 mL), cooled to 0° C. and sodium hydride (60% dispersionin oil) (24.6 mg, 0.615 mmol) added. The mixture was stirred at ambienttemperature overnight. Dichloromethane (25 mL) was added and the organicphase washed with brine (1×25 mL), then dried (Na₂SO₄), filtered andreduced in vacuo to leave a colourless gum (˜200 mg). The crude gum waspurified on a 5 g Flash silica cartridge eluting with a gradient ofheptane:ethyl acetate 6:1→1:2 to provide two products:

-   -   (c) Syn-epoxide (27b) as a viscous oil (88 mg, 0.26 mmol,        53.4%), TLC (R_(f)=0.42, EtOAc:heptane 1:1), analytical HPLC        R_(t)=15.64 min, HPLC-MS 280.1 [M+2H−Bu]⁺, 358.2 [M+Na]⁺, 693.2        [2M+Na]⁺; [□]_(D) ¹⁸−36.9° (c=8.8, CHCl₃); ¹H NMR (500 MHz,        CDCl₃ at 300K): δ 1.25 (s, C(CH₃)₃, 9H), 3.20-3.25 (dq,        CbzNHCH₂, 1H), 3.57-3.64 (m, CbzNHCH₂, 1H), 3.67-3.71 (b,        CH₂OCHCHOBu^(t)+CH₂OCHCHOBu^(t), 3H), 3.73-3.77 (m, CHOCH+CHOCH,        2H), 4.08 (d, J=10.70 Hz, CH₂OCHCHOBu^(t), 1H), 5.03-5.14 (dd,        J=12.2 Hz, OCH₂Ph, 2H), 5.22 (d, J=5.5 Hz, NH, 1H), 7.35 (bm, 5H        aromatic); ¹³C NMR (125 MHz, CDCl₃ at 300K): δ 28.38 (C(CH₃)₃),        44.22 (CbzNHCH₂), 56.71/56.83 (CHOCH+CHOCH), 66.63 (OCH₂Ph),        68.03 (CH₂OCHCHOBu^(t)), 68.23 (CH₂OCHCHOBu^(t)), 75.30        (C(CH₃)₃), 78.71 (CH₂OCHCHOBu^(t)), 128.05/128.20/128.47        (aromatic CH), 136.67 (aromatic quaternary), 156.53 (NHC(O)O).    -   (d) Bicycle alcohol (29b) as a viscous oil (33 mg, 0.10 mmol,        20.0%), TLC (R_(f)=0.13, EtOAc:heptane 1:1), analytical HPLC        R_(t)=13.66 min, HPLC-MS 236.1, 280.1 [M+2H−Bu]⁺, 358.2 [M+Na]⁺,        693.2 [2M+Na]⁺; [□]_(D) ¹⁸−22.7° (c=3.3, CHCl₃); ¹H NMR (500        MHz, CDCl₃ at 300K): δ 1.23 (s, C(CH₃)₃, 9H), 1.91/2.56 (b, OH,        0.4/0.6H), 3.06-3.14 (m, CbzNCH₂, 1H), 3.68-3.75/3.81-3.86 (dq,        J=7.7 Hz, CbzNCH₂, 0.6+0.4H), 3.75-3.80 (m, OCH₂CHOH, 1H),        4.00-4.06 (m, CHOBu^(t)+0.4 OCH₂CHOH, 1.4H), 4.09-4.14 (m,        NCHCHOH+0.6 OCH₂CHOH, 1.6H), 4.35 (b, OCH₂CHOH, 0.4H), 4.45-4.48        (m, OCH₂CHOH, 0.6H), 4.48-4.51 (m, Bu^(t)OCHCHO, 1H), 5.08-5.20        (m, OCH₂Ph, 2H), 7.35 (bm, 5H aromatic); ¹³C NMR (125 MHz, CDCl₃        at 300K): δ 28.15 (C(CH₃)₃), 48.97/49.09 (CbzNCH₂), 67.23/67.39        (OCH₂Ph), 68.23/69.23 (NCHCHOH), 70.81/71.04 (CHOBu^(t)),        74.53/74.57 (C(CH₃)₃), 74.98/75.25 (OCH₂CHOH), 77.19/77.32        (OCH₂CHOH), 81.47/82.29 (Bu^(t)OCHCHO),        127.99/128.04/128.18/128.36/128.54/128.72 (aromatic CH), 136.28        (aromatic quaternary), 154.21/155.06 (NHC(O)O).

(v) Preparation of (3R,3aR,6R,6aS)-(9H-fluoren-9-yl)methyl6-tert-butoxy-3-hydroxytetrahydro-2H-furo[3,2-b]pyrrole-4(5H)-carboxylate(3b). Alcohol (29b) (33 mg, 0.1 mmol) was dissolved in methanol (5 mL),cooled to 0° C. and 10% palladium on charcoal (15 mg) added. The mixturewas stirred, then evacuated and flushed with hydrogen. The mixture waswarmed to ambient temperature and after 1 h. filtered through celite.The filter cake was washed with ethanol (3×5 mL) and the combinedfiltrates reduced in vacuo to provide the crude amine (˜15 mg). HPLC-MS146.1 [M+2H−Bu]⁺, 202.1 [M+H]⁺, 425.2 [M+Na]⁺. The crude amine wasdissolved in 1,4-dioxane (2.5 mL) with stirring, ice-cooled and asolution of sodium carbonate (22 mg, 0.21 mmol) in water (2.5 mL) wasadded. 9-Fluorenylmethyl chloroformate (27 mg, 0.10 mmol) in 1,4-dioxane(2.5 mL) was added dropwise over 30 minutes and the mixture stirred fora further 1 h. CHCl₃ (25 mL) was then added and the organic phase washedwith 0.1N HCl (25 mL), sat. NaHCO₃ (25 mL), then brine (25 mL) and dried(Na₂SO₄). The organic layer was filtered and reduced in vacuo to leave aclear film (˜40 mg). The crude film was purified on a 5 g Flash silicacartridge eluting with a gradient of heptane:ethyl acetate 8:1→1:1 toprovide alcohol (3b) as a white solid (27.3 mg, 0.065 mmol, 65.8%). TLC(R_(f)=0.16, EtOAc:heptane 1:1), analytical HPLC R_(t)=17.39 min,HPLC-MS 368.2 [M+2H−Bu]⁺, 424.2 [M+H]⁺, 446.2 [M+Na]⁺, 869.4 [2M+Na]⁺;[□]_(D) ¹⁸−12.2° (c=2.45, CHCl₃).

(vi) Preparation of (3aS,6R,6aS)-(9H-fluoren-9-yl)methyl6-tert-butoxy-3-oxotetrahydro-2H-furo[3,2-b]pyrrole-4(5H)-carboxylate(3c). Bicycle alcohol (3b) (25 mg, 0.06 mmol) was dissolved in anhydrousdichloromethane (3 mL) with stirring under argon. Dess-Martinperiodinane (50 mg, 0.12 mmol) was added and the mixture stirredovernight. The mixture was diluted with DCM (20 mL) and washed with sat.NaHCO₃/0.25M Na₂S₂O₃, sat. NaHCO₃, brine (25 mL each) and dried(Na₂SO₄). The organic layer was filtered and reduced in vacuo to leave atan gum (˜40 mg). The crude gum was purified on a 5 g Flash silicacartridge eluting with a gradient of heptane:ethyl acetate 6:1→3:1 toprovide ketone (3c) as a white solid (21.9 mg, 0.052 mmol, 88.1%). TLC(R_(f)=0.57, EtOAc:heptane 2:1), analytical HPLC broad peak withR_(t)=17.15-19.96 min, HPLC-MS 366.1 [M+2H−Bu]⁺, 422.2 [M+H]⁺, 444.2[M+Na]⁺, 865.4 [2M+Na]⁺; [□]_(D) ¹⁸−870.5° (c=1.6, CHCl₃); ¹H NMR (500MHz, CDCl₃ at 300K): δ 1.25 (s, C(CH₃)₃, 9H), 3.30-3.40 (m, FmocNCH₂,1H), 3.61-3.66 (m, FmocNCH₂, 0.4H), 3.76-3.80 (m, FmocNCH₂, 0.6H),4.01-4.17 (m, OCH₂C(O), 2H), 4.22-4.35 (m, NCHC(O)+CHOBu^(t)+FmocCH+0.6FmocCH₂, 3.6H), 4.37-4.43 (bt, 0.4 FmocCH₂), 4.49-4.54/4.56-4.63 (m, 0.4FmocCH₂+0.6 FmocCH₂), 4.69-4.72/4.72-4.77 (m, Bu^(t)OCHCHO, 1H),7.29-7.33 (m, Fmoc H-2 and H-7), 7.38 (t, J=7.45 Hz, Fmoc H-3 and H-6),7.56 (d, J=8.7 Hz, 1.0 Fmoc H-1 or H-8), 7.65 (d, J=7.3 Hz, 0.5 Fmoc H-1or H-8), (d+m, J=7.55 Hz, Fmoc H-4 and H-5+0.5H-1 or H-8); ¹³C NMR (125MHz, CDCl₃ at 300K): δ 28.11 (C(CH₃)₃), 47.19 (FmocCH), 50.48/50.94(FmocNCH₂), 60.45/60.83 NCHC(O)), 67.64/68.23 (FmocCH₂), 71.32/71.45(OCH₂C(O)), 71.50 (CHOBu^(t)), 75.22 (C(CH₃)₃), 80.78/81.49(Bu^(t)OCHCHO), 119.88/119.95 (Fmoc C4 and C-5),124.98/125.01/125.20/125.43 (Fmoc C-1 and C-8), 127.03 (Fmoc C-2 andC-7), 127.65/127.71 (Fmoc C-3 and C-6),141.22/141.33/143.63/143.97/144.38 (Fmoc quaternary aromatics), 155.10(CH₂OC(O)N), 208.56/208.66 (C═O).

Preparation of (3aS,6S,6aS)-(9H-Fluoren-9-yl)methyl6-methoxy-3-oxotetrahydro-2H-furo[3,2-b]pyrrole-4(5H)-carboxylate (6c)

(i) Preparation of Benzyl(S)-2-((S)-2,5-dihydrofuran-2-yl)-2-methoxyethyl carbamate (30). Methyliodide (1.18 mL, 19.0 mmol) was added to a stirred mixture of alcohol(17) (1.0 g, 3.80 mmol) and silver (I) oxide (1.32 g, 5.70 mmol) inacetonitrile (15 mL). The mixture was heated at 75° C. for 3 hours thenat 80° C. for 3.5 hours. Silver (I) oxide (0.20 g, 0.86 mmol) and methyliodide (0.25 mL, 4.0 mmol) were added and heating continued for 4 hoursthen allowed to cool to ambient temperature, filtered and reduced invacuo. Flash chromatography over silica, eluting with ethylacetate:heptane mixtures 10:90 to 30:70 gave methyl ether (30) (731 mg,69%) as a colourless oil. TLC (R_(f)=0.40, EtOAc:heptane 1:1),analytical HPLC single main peak, R_(t)=13.107 min., HPLC-MS 278.1[M+H]⁺, 577.2 [2M+Na]⁺; [□]_(D) ¹⁹−100.4° (c=2.888, CHCl₃); δ_(H) (500MHz, CDCl₃) 3.20 (1H, dt, 5.67 Hz, CH₂N), 3.32-3.36 (1H, m, CHOCH₃),3.44 (3H, s, CHOCH₃), 3.42-3.49 (1H, m, CH₂N), 4.57-4.71 (2H, m,OCH₂CH═CH), 4.88-4.92 (1H, m, OCHCH═CH), 5.09 (2H, s, OCH₂Ph), 5.16 (1H,brs, NH), 5.79-5.83 and 5.95-5.99 (2H total, m, CH₂CH═CH), 7.29-7.36(5H, aromatic CH); δ_(C) (125 MHz, CDCl₃) 0.952 (CH₂NHCbz), 58.752(OCH₃), 66.705 (CH₂Ph), 75.589 (OCH₂CH═CH), 81.184 (CHOCH₃), 86.559(OCHCH═CH), 126.033, 128.097 and 128.497 (OCH₂CH═CH and Cbz aromaticCH), 136.555 (Cbz quaternary), 156.441 (Cbz C═O).

(ii) Alternative preparation of Benzyl(R)-2-((S)-2,5-dihydrofuran-2-yl)-2-methoxyethylcarbamate (30).Trimethyloxonium fluoroborate (19.12 g, 129.3 mmol) was added to astirred mixture of benzyl(S)-2-((S)-2,5-dihydrofuran-2-yl)-2-hydroxyethylcarbamate (17) (20.0 g,76.0 mmol), 4 Å molecular sieves (66 g),1,8-bis(dimethylamino)naphthalene (97.8 g, 456.2 mmol) anddichloromethane (500 mL) under an atmosphere of argon. The mixture wasstirred for 2 hours then filtered through celite in vacuo. The filtercake was washed with dichloromethane (750 mL) then the solvents removedin vacuo from the filtrate. The residue was triturated with TBME (250mL) then the granular solid removed by filtration in vacuo. The solidwas washed with TBME (3×100 mL) then the combined filtrates washed withhydrochloric acid (2.5M, 1×100 mL then 2×50 mL), brine (50 mL) thendried (Na₂SO₄), filtered and reduced in vacuo to leave a pale yellowoil. Flash chromatography over silica, eluting with ethylacetate:heptane mixtures 10:90 to 50:50 gave methylether (30) as acolourless oil (17.2 g, 82%).

(iii) Preparation of Benzyl(S)-2-((1S,2R,5S)-3,6-dioxabicyclo[3.1.0]hexan-2-yl)-2-methoxyethylcarbamate anti-(31). To a solution of methyl ether (30) (731 mg, 2.64mmol) in acetonitrile (15 mL) and aqueous Na₂.EDTA (15 mL, 0.4 mmolsolution) at 0° C. was added 1,1,1-trifluoroacetone (2.84 mL, 31.7mmol). To this solution was added in portions a mixture of sodiumbicarbonate (1.87 g, 22.2 mmol) and OXONE® (5.04 g, 8.19 mmol) over aperiod of 1.5 hours. The mixture was stirred for 15 minutes then dilutedwith water (50 mL) and the product extracted into dichloromethane (3×50mL). The combined organic layers were washed with brine (75 mL) thendried (MgSO₄), filtered and reduced in vacuo. Flash chromatography oversilica, eluting with ethyl acetate:heptane mixtures 10:90 to 30:70 gaveanti-(31) (323 mg, 42%) as a colourless oil. TLC (R_(f)=0.25,EtOAc:heptane 1:1), analytical HPLC single main peak, R_(t)=10.901 min.,HPLC-MS 294.2 [M+H]⁺, 609.3 [2M+Na]⁺; [□]_(D) ¹⁵+12.1° (c=2.890, CHCl₃);δ_(H) (500 MHz, CDCl₃) 3.27-3.55 (6H, m, CH₂NH, CHOCH₃), 3.72 and 3.78(2H, each d, 2.49 Hz respectively, OCH₂CHCH), 3.84 (1H, d, J=9.98 Hz,OCH₂CH), 3.94 (1H, d, J=10.02 Hz, OCH₂CH), 4.12 (1H, d, J=2.76 Hz,OCHCHOCH₃), 5.10 (2H, s, CH₂Ph), 5.27 (1H, brs, NH), 7.28-7.37 (5H, m,phenyl CH); δ_(C) (125 MHz, CDCl₃) 40.819 (CH₂NHCbz), 56.769 and 57.700(OCH₂CHCH), 58.442 (OCH₃), 66.784 (CH₂Ph), 68.446 (OCH₂CH), 78.631(OCHCHOCH₃), 79.264 (CHOCH₃), 128.079, 128.160 and 128.521 (aromaticCH), 136.451 (Cbz quaternary), 156.532 (Cbz C═O).

(iv) (3R,3aR,6S,6aS)-(9H-Fluoren-9-yl)methyl3-hydroxy-6-methoxytetrahydro-2H-furo[3,2-b]pyrrole-4(5H)-carboxylate(6b). Ethanol (15 mL) was added dropwise to a mixture of 10% palladiumon charcoal (30 mg) and anti-(31) (315 mg, 1.07 mmol) under anatmosphere of argon. The argon was replaced by hydrogen then thesuspension was stirred for 1.5 hours then 10% palladium on charcoal (30mg) was added. The mixture was stirred for 2 hours then 10% palladium oncharcoal (50 mg) was added. The mixture was stirred for 4.5 hours thenfiltered through celite in vacuo. The filter cake was washed withethanol then the solvents removed in vacuo from the filtrate to obtainthe crude (3R,3aR,6S,6aS)-6-methoxyhexahydro-2H-furo[3,2-b]pyrrol-3-olwhich was used without further purification.

A solution of sodium carbonate (239 mg, 2.26 mmol) in water (10 mL) wasadded whilst stirring to a solution of(3R,3aR,6S,6aS)-6-methoxyhexahydro-2H-furo[3,2-b]pyrrol-3-ol in1,4-dioxane (7 mL). A solution of 9-fluorenylmethoxycarbonyl chloride(319 mg, 1.23 mmol) in 1,4-dioxane (3 mL) was added then the mixturestirred for 40 minutes then water (30 mL) was added and the productextracted into dichloromethane (1×40 mL then 2×30 mL). The organic layerwas washed with brine (50 mL), then dried (MgSO₄), filtered and reducedin vacuo to leave a residue. Flash chromatography over silica, elutingwith ethyl acetate:heptane mixtures 7:93 to 45:55 gave bicyclic alcohol(6b) (270 mg, 66%) as a white solid. TLC (R_(f)=0.34, EtOAc:heptane3:2), analytical HPLC single main peak, R_(t)=15.990 min., HPLC-MS 382.1[M+H]⁺, 404.1 [M+Na]⁺, 785.3 [2M+Na]⁺; [□]_(D) ^(18.5)−35.4° (c=2.758,CHCl₃); δ_(H) (500 MHz, CDCl₃) mixture of rotamers major:minor 3:2; 1.02(0.6H, d, J=3.55 Hz, OH major), 2.59 (0.40H, d, J=3.19 Hz, OH minor),3.10 (0.6H, dd, 3.89 Hz, FmocNCH₂ major), 3.26 (1.8H, s, OCH₃ major),3.30 (0.4H, dd, 4.19 Hz, FmocNCH₂ minor), 3.35 (1.2H, s, OCH₃ minor),3.49 (0.6H, m, OCH₂CHOH major), 3.52 (0.6H, dd, 1.81 Hz, OCH₂CHOHmajor), 3.55-3.59 (1.2H, m, OCH₂CHOH major and FmocNCH major), 3.64(0.6H, d, J=3.69 Hz, CHOCH₃ major), 3.65-3.70 (1H, m, FmocNCH₂),3.75-3.79 (0.8H, m, OCH₂CHOH minor and CHOCH₃ minor), 3.85 (0.4H, dd,J=9.85 and 4.46 Hz, OCH₂CHOH minor), 4.22-4.26 (1.4H, m, FmocNCH minorand Fmoc CH), 4.37 (0.6H, d, J=4.64 Hz, OCHCHOCH₃ major), 4.40-4.44(1.2H, m, Fmoc CH₂ minor and OCH₂CHOH minor), 4.60 (0.4H, d, J=4.94 Hz,OCHCHOCH₃ minor), 4.70 (0.6H, dd, J=10.80 and 3.96 Hz, Fmoc CH₂ major),4.82 (0.6H, dd, 4.25 Hz, Fmoc CH₂ major), 7.29-7.80 (8H, Fmoc aromaticCH); δ_(C) (125 MHz, CDCl₃) 47.248/47.378 (Fmoc CH), 49.754/50.177(FmocNCH₂), 56.868/56.996 (OCH₃), 65.736/67.270 (Fmoc CH₂),68.262/69.085 (FmocNCH), 73.760/74.008 (OCH₂CHOH), 75.812/76.145(OCH₂CHOH), 81.509/82.286 (OCHCHOCH₃), 83.496/84.166 (OCHCHOCH₃),119.805, 119.982, 120.003, 124.494, 124.576, 124.958, 124.975, 127.019,127.034, 127.404, 127.488, 127.637, 127.726, 127.754 and 127.865 (Fmocaromatic CH), 143.633, 143.909, 143.943 and 144.037 (Fmoc quaternary),154.255/155.025 (Fmoc C═O).

(v) (3aS,6S,6aS)-(9H-Fluoren-9-yl)methyl6-methoxy-3-oxotetrahydro-2H-furo[3,2-b]pyrrole-4(5H)-carboxylate (6c).Dess-Martin periodinane (600 mg, 1.42 mmol) was added to a stirredsolution of bicyclic alcohol (6b) (270, 0.71 mmol) in dichloromethane(10 mL) at 0° C. under an atmosphere of argon. The mixture was allowedto warm to ambient temperature over 2 hours then Dess-Martin periodinane(300 mg, 0.71 mmol) added. The mixture was stirred for 4 hours thendiluted with dichloromethane (20 mL). The organic phase was washed witha mixture of saturated aqueous sodium bicarbonate and 0.25M sodiumthiosulphate solution (1:1, 15 mL), then saturated aqueous sodiumbicarbonate (10 mL), then brine (10 mL), then dried (MgSO₄), filteredand reduced in vacuo. Flash chromatography over silica, eluting withethyl acetate:heptane mixtures 15:85 to 40:60 gave bicyclic ketone (6c)(200 mg, 74%) as a white solid. TLC (R_(f)=0.45, EtOAc:heptane 7:3),analytical HPLC broad main peak, R_(t)=15.676-16.668 min., HPLC-MS 380.2[M+H]⁺, 781.3 [2M+Na]⁺; [□]_(D) ¹⁷−105.6° (c=9.468, CHCl₃); δ_(H) (500MHz, CDCl₃) mixture of rotamers approx. 1:1; 3.33 (1.5H, s, OCH₃), 3.38(1.5H, s, OCH₃), 3.42-3.49 (1H, m, FmocNCH₂), 3.82 (0.5H, d, J=12.07 Hz,FmocNCH₂), 3.89-4.01 (2H, m, OCHCHOMe and OCH₂C═O), 4.05-4.19 (1.5H, m,OCH₂C═O and FmocNCH₂), 4.21-4.34 (1.5H, m, Fmoc-CH₂ and Fmoc-CH),4.37-4.40 (1H, m, FmocNCH), 4.42-4.56 (1.5H, m, Fmoc-CH₂), 4.74 (0.5H,d, J=4.33 Hz, OCHCHOCH₃), 4.79 (1H, d, J=4.14 Hz, OCHCHOCH₃), 7.28-7.76(8H, Fmoc aromatic CH); δ_(C) (125 MHz, CDCl₃); 47.104/47.156 (Fmoc-CH),49.957 (FmocNCH₂), 56.975/57.031 (OCH₃), 60.853/61.278 (FmocNCH),67.649/68.476 (Fmoc-CH₂), 70.078 (OCH₂C═O), 81.701/82.335 (OCHCHOCH₃),83.549/84.751 (OCHCHOCH₃), 119.894, 119.962, 124.963, 125.226, 125.524,127.029, 127.065 and 127.695 (Fmoc aromatic CH), 141.238, 141.309,143.654, 143.811 and 144.354 (Fmoc quaternary), 155.065/155.203 (FmocC═O), 207.830/207.992 (ketone C═O).

Preparation of (3R,3aR,6S,6aS)-Benzyl3-hydroxy-6-methoxytetrahydro-2H-furo[3,2-b]pyrrole-4(5H)-carboxylate(72)

Sodium hydride (60% dispersion in oil, 800 mg, 19.95 mmol) was addedover 1 minute to a stirred solution consisting of a 4:1 mixture ofanti-epoxide benzyl(S)-2-((1S,2R,5S)-3,6-dioxabicyclo[3.1.0]hexan-2-yl)-2-methoxyethylcarbamate (31) and syn-epoxide benzyl(S)-2-((1R,2R,5R)-3,6-dioxabicyclo[3.1.0]hexan-2-yl)-2-methoxyethylcarbamate (4.5 mg, 15.35 mmol total) in tetrahydrofuran (15 mL) at 0° C.under an atmosphere of argon. The mixture was stirred at 0° C. for 30minutes then at ambient temperature overnight then dichloromethane (150mL) added. The organic layer was washed with brine (75 mL), then dried(Na₂SO₄), filtered and reduced in vacuo to leave a residue (5.8 g). Theresidue was treated 4N HCl in dioxin (18 mL, 75 mmol) for 1 h thenreduced in vacuo. Flash chromatography over silica, eluting with ethylacetate:heptane mixtures 25:75 to 50:50 gave (3R,3aR,6S,6aS)-benzyl3-hydroxy-6-methoxytetrahydro-2H-furo[3,2-b]pyrrole-4(5H)-carboxylate(72) as a straw coloured oil (2.20 g, 7.5 mmol). TLC (R_(f)=0.30,EtOAc:heptane 3:2), analytical HPLC single main peak, R_(t)=9.50 min.;HPLC-MS 294.1 [M+H]⁺, 609.2 [2M+Na]⁺; [□]_(D) ^(22.0)−49.6° (c=2.52,CHCl₃).

(vii) Alternative Preparation of (3R,3aR,6S,6aS)-Benzyl3-hydroxy-6-methoxytetrahydro-2H-furo[3,2-b]pyrrole-4(5H)-carboxylate(72). Ethanol (100 mL) was added dropwise to a mixture of 10% palladiumon charcoal (400 mg) and benzyl(S)-2-((1S,2R,5S)-3,6-dioxabicyclo[3.1.0]hexan-2-yl)-2-methoxyethylcarbamate (31) (4.0 g, 13.65 mmol) under an atmosphere of argon. Theargon was replaced by hydrogen then the suspension was stirred for 15hours then filtered through celite in vacuo. The filter cake was washedwith ethanol then the solvents removed in vacuo from the filtrate toobtain the crude(3R,3aR,6S,6aS)-6-methoxyhexahydro-2H-furo[3,2-b]pyrrol-3-ol which wasused without further purification.

A solution of sodium carbonate (3.04 g, 28.7 mmol) in water (20 mL) wasadded whilst stirring to a solution of(3R,3aR,6S,6aS)-6-methoxyhexahydro-2H-furo[3,2-b]pyrrol-3-ol (preparedas above, assumed to be 13.65 mmol) in 1,4-dioxane (50 mL). Benzylchloroformate (2.88 mL, 20.48 mmol) was added dropwise then the mixturestirred for 6 hours, then water (200 mL) was added and the productextracted into dichloromethane (3×75 mL). The organic layer was dried(Na₂SO₄), filtered and reduced in vacuo to leave a colourless oil (4.95g). Flash chromatography over silica, eluting with ethyl acetate:heptanemixtures 15:85 to 75:25 gave (3R,3aR,6S,6aS)-benzyl3-hydroxy-6-methoxytetrahydro-2H-furo[3,2-b]pyrrole-4(5H)-carboxylate(72) (2.98 g, 74%) as a colourless oil. TLC (R_(f)=0.47, EtOAc:heptane2:1), analytical HPLC single main peak, R_(t)=9.78 min., HPLC-MS 294.1[M+H]⁺, 316.1 [M+Na]⁺, 609.2 [2M+Na]⁺; δ_(H) (500 MHz, CDCl₃) mixture ofrotamers major:minor 3:2; 3.29 (0.4H, dd, 3.87 Hz, 1×CbzNCH₂ minor),3.34 (3H, s, OCH₃), 3.34-3.38 (0.6H, m, 1×CbzNCH₂ major), 3.69-3.97 (4H,m, 1×CbzNCH₂, OCH₂CHOH and CHOMe), 4.26 (1H, brt, J=5.55 Hz, OCHCHOCH₃),4.37 (0.4H, brs, OCH₂CHOH minor), 4.49 (0.6H, brs, OCH₂CHOH major), 4.61(1H, d, J=4.89 Hz, CbzNCH), 5.09-5.24 (2H, m, CH₂Ph), 7.30-7.40 (5H, m,aromatic CH); δ_(C) (125 MHz, CDCl₃) 50.14/50.41 (CbzNCH₂), 56.97/57.03(OCH₃), 67.26/67.38 (CH₂Ph), 68.15/69.14 (CbzNCH), 74.05/74.34(OCH₂CHOH), 75.79/76.59 (OCH₂CHOH), 81.64/82.34 (OCHCHOCH₃), 83.47/84.59(OCHCHOCH₃), 127.91, 127.96, 128.13/128.26/128.52/128.56/128.67 and128.80 (aromatic CH), 136.26/136.32 (aromatic quaternary), 154.50/155.13(Cbz C═O).

Preparation of (3aS,6R,6aS)-(9H-Fluoren-9-yl)methyl6-methoxy-3-oxotetrahydro-2H-furo[3,2-b]pyrrole-4(5H)-carboxylate (5c)

(i) Preparation of Benzyl(R)-2-((S)-2,5-dihydrofuran-2-yl)-2-methoxyethyl carbamate (30b). Methyliodide (1.89 mL, 30.4 mmol) was added to a stirred mixture of alcohol(18) (2.0 g, 7.59 mmol) and silver (I) oxide (2.64 g, 11.4 mmol) inacetonitrile (32 mL). The mixture was heated at 72° C. for 3 hours thenstood at ambient temperature for 16 hours. Heating was continued for 1.5hours at 72° C. then the mixture allowed to cool to ambient temperature,filtered and reduced in vacuo. Flash chromatography over silica, elutingwith an ethyl acetate:heptane mixture 1:1 to give methyl ether (30b)(1.05 g, 50%) with an estimated purity of 93%, as a colourless oiltogether with recovered alcohol (18) (694 mg, 35%). Data for methylether (30b); TLC (R_(f)=0.35, EtOAc:heptane 1:1), analytical HPLC mainpeak, R_(t)=13.082 min., HPLC-MS 278.1 [M+H]⁺, 577.2 [2M+Na]⁺; [□]_(D)¹⁸−54.5° (c=3.487, CHCl₃); δ_(H) (500 MHz, CDCl₃) 3.22-3.27, (2H, m,CH₂N and CHOCH₃), 3.42 (3H, s, CHOCH₃), 3.44-3.53 (1H, m, CH₂N),4.58-4.67 (2H, m, OCH₂CH═CH), 4.88 (1H, m, OCHCH═CH), 5.09 (2H, s,OCH₂Ph), 5.18 (1H, brs, NH), 5.80-5.84 and 5.97-6.00 (2H total, m,CH₂CH═CH), 7.29-7.36 (5H, m, aromatic CH); δ_(C) (125 MHz, CDCl₃) 40.634(CH₂NHCbz), 58.141 (OCH₃), 66.697 (CH₂Ph), 75.621 (OCH₂CH═CH), 81.912(CHOCH₃), 86.193 (OCHCH═CH), 126.506, 128.084, 128.100, 128.328, and128.491 (OCH₂CH═CH and Cbz aromatic CH), 136.563 (Cbz quaternary),156.481 (Cbz C═O).

(ii) Alternative preparation of Benzyl(R)-2-((S)-2,5-dihydrofuran-2-yl)-2-methoxyethylcarbamate (30b).Trimethyloxonium fluoroborate (2.16 g, 14.61 mmol) was added to astirred mixture of benzyl(R)-2-((S)-2,5-dihydrofuran-2-yl)-2-hydroxyethylcarbamate (18) (2.26 g,8.59 mmol), 4 Å molecular sieves (7.1 g),1,8-bis(dimethylamino)naphthalene (11.0 g, 51.6 mmol) anddichloromethane (55 mL) under an atmosphere of argon. The mixture wasstirred for 2 hours then filtered through celite in vacuo. The filtercake was washed with dichloromethane (300 mL) then the solvents removedin vacuo from the filtrate. The residue was triturated with diethylether (100 mL) then the yellow solid removed by filtration in vacuo. Thesolid was washed with diethyl ether (100 mL) then the combined filtrateswashed with hydrochloric acid (2.5M, 1×50 mL then 2×25 mL), brine (50mL) then dried (Na₂SO₄), filtered and reduced in vacuo to leave a paleyellow oil (1.93 g). Flash chromatography over silica, eluting withethyl acetate:heptane mixtures 5:95 to 50:50 gave methylether (30b) as acolourless oil (1.42 g, 60%).

(iii) Preparation of Benzyl(R)-2-((1S,2R,5S)-3,6-dioxabicyclo[3.1.0]hexan-2-yl)-2-methoxyethylcarbamate anti-(31b). To a solution of methyl ether (30b) (1.0 g, 3.61mmol) in acetonitrile (20 mL) and aqueous Na₂.EDTA (20 mL, 0.4 mmolsolution) at 0° C. was added 1,1,1-trifluoroacetone (3.87 mL, 43.3mmol). To this solution was added in portions a mixture of sodiumbicarbonate (2.54 g, 30.3 mmol) and OXONE® (6.87 g, 11.2 mmol) over aperiod of 1.5 hours. The mixture was stirred for 30 minutes then dilutedwith water (50 mL) and the product extracted into dichloromethane (3×50mL). The combined organic layers were washed with brine (60 mL) thendried (Na₂SO₄), filtered and reduced in vacuo. Flash chromatography oversilica, eluting with ethyl acetate:heptane mixtures 7:93 to 50:50 gave a3:1 mixture of anti-(31b) and syn-epoxide benzyl(R)-2-((1R,2R,5R)-3,6-dioxabicyclo[3.1.0]hexan-2-yl)-2-methoxyethylcarbamate respectively (611 mg, 58%) as a colourless oil. TLC(R_(f)=0.25, EtOAc:heptane 1:1), analytical HPLC two main peaks,R_(t)=11.792 and 12.132 min. (approx. 3:1 respectively). HPLC-MS 294.2[M+H]⁺, 316.1 [M+Na]⁺, 609.3 [2M+Na]⁺.

(iv) (3R,3aR,6R,6aS)— (9H-Fluoren-9-yl)methyl3-hydroxy-6-methoxytetrahydro-2H-furo[3,2-b]pyrrole-4(5H)-carboxylate(5b). Ethanol (30 mL) was added dropwise to a mixture of 10% palladiumon charcoal (200 mg) and syn-/anti-epoxides respectively (605 mg, 2.06mmol) under an atmosphere of argon. The argon was replaced by hydrogenthen the suspension was stirred for 2.5 hours then filtered throughcelite in vacuo. The filter cake was washed with ethanol then thesolvents removed in vacuo from the filtrate to obtain the crude(3R,3aR,6R,6aS)-6-methoxyhexahydro-2H-furo[3,2-b]pyrrol-3-ol which wasused without further purification.

A solution of sodium carbonate (459 mg, 4.33 mmol) in water (20 mL) wasadded whilst stirring to a solution of(3R,3aR,6R,6aS)-6-methoxyhexahydro-2H-furo[3,2-b]pyrrol-3-ol in1,4-dioxane (20 mL). A solution of 9-fluorenylmethoxycarbonyl chloride(614 mg, 2.37 mmol) in 1,4-dioxane (3 mL) was added then the mixturestirred for 1.5 hours then water (30 mL) was added and the productextracted into dichloromethane (3×50 mL). The organic layer was washedwith brine (70 mL), then dried (Na₂SO₄), filtered and reduced in vacuoto leave a residue. Flash chromatography over silica, eluting with ethylacetate:heptane mixtures 10:90 to 80:20 gave (in order of elution)syn-epoxide (9H-fluoren-9-yl)methyl(R)-2-((1R,2R,5R)-3,6-dioxabicyclo[3.1.0]hexan-2-yl)-2-methoxyethylcarbamate (111 mg, 14%) as a colourless oil and bicyclic alcohol (5b)(453 mg, 58%) as a white solid. Data for syn-epoxide; TLC (R_(f)=0.22,EtOAc:heptane 1:1), analytical HPLC single main peak, R_(t)=17.108 min.;HPLC-MS 382.2 [M+H]⁺, 404.2 [2M+Na]⁺; [□]_(D) ¹⁹−24.5° (c=6.120, CHCl₃);δ_(H) (500 MHz, CDCl₃) 3.37-3.56 (3H, m, CHOCH₃ and CH₂NH), 3.49 (3H, s,OCH₃ major), 3.71 (1H, d, J=10.63 Hz, OCH₂CH), 3.75 (1H, d, J=7.48 Hz,OCHCHOCH₃), 3.79-3.84 (2H, m, OCH₂CHCH), 4.04 (1H, d, J=10.67 Hz,OCH₂CH), 4.23 (1H, t, J=6.97 Hz, Fmoc CH), 4.38 (2H, d, J=7.12 Hz, FmocCH₂), 5.16 (1H brs, NH), 7.29-7.76 (8H, Fmoc aromatic CH); δ_(C) (125MHz, CDCl₃), 40.837 (CH₂NHFmoc), 47.259 (Fmoc CH), 56.424/56.648(OCH₂CHCH), 58.047 (OCH₃), 66.688 (Fmoc CH₂), 67.700 (OCH₂CH), 77.573(OCHCHOCH₃), 78.238 (CHOCH₃), 119.932, 125.088, 126.998 and 127.617(Fmoc aromatic CH), 141.277, 143.021 and 144.021 (Fmoc quaternary),156.521 (Cbz C═O). Data for bicyclic alcohol (5b); TLC (R_(f)=0.05,EtOAc:heptane 1:1), analytical HPLC single main peak, R_(t)=15.004 min.,HPLC-MS 382.2 [M+H]⁺, 404.2 [M+Na]⁺, 785.3 [2M+Na]⁺; [□]_(D) ¹⁶−10.0°(c=4.016, CHCl₃); δ_(H) (500 MHz, CDCl₃) mixture of rotamers major:minor4:3; 0.96 (0.57H, d, J=3.54 Hz, OH major), 2.51 (0.43H, d, J=3.50 Hz, OHminor), 2.93 (0.57H, t, J=10.12 Hz, FmocNCH₂ major), 3.07-3.15 (0.43H,m, FmocNCH₂ minor), 3.36 (1.71H, s, OCH₃ major), 3.41 (1H, brd, J=4.63Hz, FmocNCH major), 3.46 (1.29H, s, OCH₃ minor), 3.48-3.52 (0.57H, m,OCH₂CHOH major), 3.56-3.64 (1.14H, m, CHOCH₃ major and OCH₂CHOH major),3.73-3.86 (2.43H, m, OCH₂CHOH, FmocNCH₂ and CHOCH₃ minor), 4.00 (0.43H,dd, 9.90 Hz, OCH₂CHOH minor), 4.16 (1H, dd, 1.09 Hz, FmocNCH minor),4.20-4.25 (1H, m, Fmoc CH), 4.38-4.43 (0.86H, m, OCHOH minor and 1×FmocCH₂ minor), 4.45 (0.57H, t, J=4.29 Hz, CHCHOCH₃ major), 4.49 (0.43H, dd,6.82 Hz, Fmoc CH₂ minor), 4.69-4.73 (0.43H, m, OCHCHOCH₃ minor), 4.75(0.57H, dd, 3.74 Hz, Fmoc CH₂ major), 4.81 (0.57H, dd, 4.01 Hz, Fmoc CH₂major), 7.28-7.81 (8H, Fmoc aromatic CH); δ_(C) (125 MHz, CDCl₃)47.276/47.369 (Fmoc CH), 47.504/47.898 (FmocNCH₂), 57.788/57.839 (OCH₃),65.761/67.333 (Fmoc CH₂), 68.812/69.338 (FmocNCH), 74.940/75.145(OCH₂CHOH), 76.276/76.746 (OCH₂CHOH), 78.834/79.335 (OCHCHOCH₃),78.994/79.507 (OCHCHOCH₃), 119.859, 119.895, 120.036, 124.389, 124.442,124.877, 124.960, 127.035, 127.059, 127.451, 127.494, 127.803, 127.89and 127.941 (Fmoc aromatic CH), 141.348, 141.373, 141.434, 143.585,143.585, 143.729, 143.911 and 143.947 (Fmoc quaternary), 153.937/154.896(Fmoc C═O).

(v) (3aS,6R,6aS)-(9H-Fluoren-9-yl)methyl6-methoxy-3-oxotetrahydro-2H-furo[3,2-b]pyrrole-4(5H)-carboxylate (5c).Dess-Martin periodinane (985 mg, 2.32 mmol) was added to a stirredsolution of bicyclic alcohol (5b) (443 mg, 1.16 mmol) in dichloromethane(17 mL) at 0° C. under an atmosphere of argon. The mixture was stirredfor 2 hours then allowed to warm to ambient temperature then stirred for2 hours, then diluted with dichloromethane (30 mL). The organic phasewas washed with a mixture of saturated aqueous sodium bicarbonate and0.5M sodium thiosulphate solution (1:1, 30 mL), then saturated aqueoussodium bicarbonate (20 mL), then brine (20 mL), then dried (Na₂SO₄),filtered and reduced in vacuo. Flash chromatography over silica, elutingwith ethyl acetate:heptane mixtures 20:80 to 40:60 gave bicyclic ketone(5c) (305 mg, 69%) as a white solid. TLC (R_(f)=0.50, EtOAc:heptane3:1), analytical HPLC broad main peak, R_(t)=14.547-17.583 min., HPLC-MS380.2 [M+H]⁺, 781.3 [2M+Na]⁺; [□]_(D) ^(16.5)−95.5° (c=2.565, CHCl₃);δ_(H) (500 MHz, CDCl₃) mixture of rotamers approx. 1:1; 3.46 (3H, s,OCH₃), 3.42-3.53 (1H, m, FmocNCH₂), 3.64-3.70 (0.5H, m, FmocNCH₂),3.75-3.81 (0.5H, m, FmocNCH₂), 3.90-3.95 (1H, m, OCHCHOMe), 4.09-4.15(1H, m, OCH₂C═O), 4.20-4.35 (3H, m, 1×Fmoc CH, 1×OCH₂C═O, 0.5×FmocNCH,and 0.5×Fmoc CH₂), 4.38-4.44 (1H, m, FmocNCH and Fmoc CH₂), 4.50-4.61(1H, m, Fmoc CH₂), 4.88-4.91 (1H, m, OCHCHOCH₃), 7.28-7.77 (8H, Fmocaromatic CH); δ_(C) (125 MHz, CDCl₃); 46.944/47.188 (Fmoc CH),48.972/49.088 (FmocNCH₂), 58.036 (OCH₃), 60.295/60.704 (FmocNCH),67.746/68.277 (Fmoc CH₂), 71.427 (OCH₂C═O), 79.339/80.093 (OCHCHOCH₃),79.424/80.241 (OCHCHOCH₃), 119.904, 119.993, 120.191, 124.990, 125.190,125.380, 127.053, 127.094, 127.734, 127.848 and 128.038 (Fmoc aromaticCH), 141.302, 143.604, 143.910 and 144.285 (Fmoc quaternary), 155.141(Fmoc C═O), 208.397/208.594 (ketone C═O).

Preparation of (3R,3aR,6R,6aS)-Benzyl3-hydroxy-6-methoxytetrahydro-2H-furo[3,2-b]pyrrole-4(5H)-carboxylate(73)

Sodium hydride (60% dispersion in oil, 164 mg, 4.11 mmol) was added over1 minute to a stirred solution consisting of an ˜4:1 mixture ofanti-epoxide benzyl(R)-2-((1S,2R,5S)-3,6-dioxabicyclo[3.1.0]hexan-2-yl)-2-methoxyethylcarbamate (31b) and syn-epoxide benzyl(R)-2-((1R,2R,5R)-3,6-dioxabicyclo[3.1.0]hexan-2-yl)-2-methoxyethylcarbamate (963 mg, 3.29 mmol total) in tetrahydrofuran (10 mL) at 0° C.under an atmosphere of argon. The mixture was stirred at 0° C. for 30minutes then at ambient temperature for 2.75 hours then dichloromethane(150 mL) added. The organic layer was washed with brine (75 mL), thendried (Na₂SO₄), filtered and reduced in vacuo to leave a residue (1.0g). Flash chromatography over silica, eluting with ethyl acetate:heptanemixtures 30:70 to 90:10 gave (3R,3aR,6R,6aS)-benzyl3-hydroxy-6-methoxytetrahydro-2H-furo[3,2-b]pyrrole-4(5H)-carboxylate(73) as a colourless oil (657 mg, 85% based on anti-epoxide). TLC(R_(f)=0.30, EtOAc:heptane 2:1), analytical HPLC single main peak,R_(t)=8.70 min.; HPLC-MS 294.1 [M+H]⁺, 609.2 [2M+Na]⁺; [□]_(D)^(23.0)−29.4° (c=2.38, CHCl₃); δ_(C) (125 MHz, CDCl₃) 47.93/48.02(CbzNCH₂), 57.87/57.90 (OCH₃), 67.39/67.46 (CH₂Ph), 68.43/69.40(CbzNCH), 75.24/75.41 (OCH₂CHOH), 76.07 (OCH₂CHOH),78.88/79.22/79.56/79.72 (OCHCHOCH₃)+(OCHCHOCH₃),127.96/128.03/128.17/128.24/128.35/128.55/128.69 (aromatic CH),136.06/136.18 (aromatic quaternary), 154.19/155.02 (Cbz C═O).

Preparation of (3aS,6S,6aR)-(9H-fluoren-9-yl)methyl6-(tert-butoxycarbonylamino)-3-oxotetrahydro-2H-furo[3,2-b]pyrrole-4(5H)-carboxylate(8c)

(i) Preparation of (3R,3aR,6R,6aS)— Benzyl3-hydroxy-6-(tosyloxy)tetrahydro-2H-furo[3,2-b]pyrrole-4(5H)-carboxylate(34b). Ethanol (1.5 mL) was added dropwise to a mixture of 10% palladiumon charcoal (10 mg) and anti-(33b) (12.0 mg, 0.028 mmol) under anatmosphere of argon. The argon was replaced by hydrogen then thesuspension was stirred for 1.75 hours before filtering the mixturethrough celite in vacuo. The filter cake was washed with ethanol (7.5mL) then the solvents removed in vacuo from the filtrate. The residuewas azeotroped with toluene (2 mL) to obtain(3R,3aR,6R,6aS)-3-hydroxyhexahydro-2H-furo[3,2-b]pyrrol-6-yl4-methylbenzenesulfonate (7.6 mg, 89%) as a pale yellow oil which wasused without further purification. TLC (R_(f)=0.01, EtOAc:heptane 1:1),HPLC-MS 300.1 [M+H]⁺, 621.2 [2M+Na]⁺.

A solution of sodium carbonate (6.2 mg, 0.058 mmol) in water (0.15 mL)was added whilst stirring to a solution of(3R,3aR,6R,6aS)-3-hydroxyhexahydro-2H-furo[3,2-b]pyrrol-6-yl4-methylbenzenesulfonate in 1,4-dioxane (0.3 mL). Benzylchloroformate(5.9 μL, 0.042 mmol) was added then the mixture stirred for 2 hours.Water (5 mL) was added and the product extracted into dichloromethane(2×5 mL). The organic layer was washed with brine (5 mL), then dried(Na₂SO₄), filtered and reduced in vacuo to leave a residue (10.6 mg).Flash chromatography over silica, eluting with ethyl acetate:heptanemixtures 20:80 to 50:50 gave bicyclic alcohol (34b) (6.6 mg, 54%) as awhite solid. TLC (R_(f)=0.20, EtOAc:heptane 1:1), analytical HPLC singlemain peak, R_(t)=17.32 min., HPLC-MS 434.1 [M+H]⁺, 889.2 [2M+Na]⁺;[□]_(D) ^(23.0)−25.7° (c=2.53, CHCl₃); δ_(H) (500 MHz, CDCl₃) mixture ofrotamers major:minor 2:1; 2.01 (0.33H, brs, OH minor), 2.43 (3H, s,aryl-CH₃), 2.77 (0.66H, brs, OH major), 3.18-3.24 (0.33H, m, CbzNCH₂minor), 3.33-3.38 (0.66H, m, CbzNCH₂ major), 3.79-3.85 (1H, m,OCH₂CHOH), 3.86-3.91 (1H, m, CbzNCH₂), 3.92-3.96 (0.33H, m, OCH₂CHOHminor), 3.96-4.01 (0.66H, m, OCH₂CHOH major), 4.13-4.16 (1H, m, CbzNCH),4.35 (0.33H, m, OCH₂CHOH minor), 4.45 (0.66H, m, OCH₂CHOH major), 4.56(0.33H, t, J=4.64 Hz, TsOCHCH, minor), 4.64 (0.66H, t, J=4.36 Hz,TsOCHCH, major), 4.71-4.78 (1H, m, TsOCHCH), 5.06-5.17 (2H, m, CH₂Ph),7.31-7.38 (7H, m, phenyl CH and aromatic CH₃CCH), 7.80 (2H, d, J=8.33Hz, aromatic OSO₂CCH); δ_(C) (125 MHz, CDCl₃) 21.683 (aryl-CH₃),47.384/47.855 (CbzNCH₂), 67.636/67.717 (CH₂Ph), 68.042/68.817 (CbzNCH),75.525/75.967 (OCH₂CHOH), 75.967/76.836 (OCH₂CHOH), 76.068/76.401(TsOCHCH), 79.342/80.208 (TsOCHCH), 127.965, 128.107, 128.382, 128.510,128.605, 128.753, 129.940 and 129.997 (aromatic CH), 132.991 (CHOSO₂Cquaternary), 135.779/135.869 (Cbz quaternary), 145.319 (CH₃Cquaternary), 153.862/154.751 (Cbz C═O).

(ii) Preparation of (3R,3aR,6S,6aS)-benzyl6-azido-3-hydroxytetrahydro-2H-furo[3,2-b]pyrrole-4(5H)-carboxylate(36b). Sodium azide (15 mg, 0.231 mmol) was added to a stirred solutionof bicyclic alcohol (34b) (50 mg, 0.115 mmol) in dimethylformamide (1mL) under an atmosphere of argon. The mixture was heated at 70° C. for18 hours then sodium azide (10 mg, 0.154 mmol) was added and heatingcontinued at 105° C. for 21 hours. Water (6 mL) was added and theproduct extracted into tert-butyl methyl ether (3×3 mL). The organiclayer was washed with brine (9 mL), then dried (Na₂SO₄), filtered andreduced in vacuo to leave a residue (56 mg). Flash chromatography oversilica, eluting with ethyl acetate:pentane mixtures 1:2 gave bicyclicazidoalcohol (36b) (28 mg, 80%) as a (viscous) colourless oil. TLC(R_(f)=0.25, EtOAc:heptane 1:1), analytical HPLC single main peak,R_(t)=13.43 min., HPLC-MS 277.2 [M−N₂+H]⁺, 327.2 [M+Na]⁺, 631.3[2M+Na]⁺; [□]_(D) ¹⁷−22.4° (c=1.56, CHCl₃); δ_(H) (500 MHz, CDCl₃)mixture of rotamers major:minor 2:1; 1.9 and 3.2 (approx. 1H total, eachbrs, OH), 3.39-3.45 (1H, m, CbzNCH₂), 3.74 (0.66H, d, J=12.37 Hz,CbzNCH₂, major), 3.78-3.91 (2H, m, OCH₂CHOH), 3.87 (0.33H, J=12.24 Hz,CbzNCH₂, minor), 4.02 (1H, d, J=4.21 Hz, CHN₃), 4.28 (0.33H, d, J=4.45Hz, CbzNCH minor), 4.30 (0.66H, d, J=4.58 Hz, CbzNCH major), 4.39(0.33H, brs, OCH₂CHOH minor), 4.50 (0.66H, brs, OCH₂CHOH major), 4.61(1H, d, J=4.56 Hz, CHCHN₃), 5.13 (0.33H, d, J=12.08 Hz, CH₂Ph minor),5.13 (1.322H, s, CH₂Ph major), 5.23 (0.33H, d, J=12.27 Hz, CH₂Ph minor),7.30-7.38 (5H, m, phenyl CH); δ_(C) (125 MHz, CDCl₃) 50.000/50.282(CbzNCH₂), 62.823/63.317 (CHN₃), 67.601 (CH₂Ph), 68.013/68.998 (CbzNCH),74.633/74.660 (OCH₂CHOH), 75.378/76.251 (OCH₂CHOH), 84.223/85.159(CHCHN₃), 127.959, 127.976, 128.292, 128.368, 128.587 and 128.715(aromatic CH), 135.933/136.109 (Cbz quaternary), 154.172/154.808 (CbzC═O).

(iii) Preparation of (3R,3aR,6S,6aS)-benzyl6-(tert-butoxycarbonylamino)-3-hydroxytetrahydro-2H-furo[3,2-b]pyrrole-4(5H)-carboxylate(37b).

(a) Reduction of azide. Azide (36b) (54 mg, 0.177 mmol) was dissolved inTHF (6 mL) with stirring and water (32 □L, 1.77 mmol) added followed bytriphenylphosphine (70 mg, 0.266 mmol). The mixture was heated at 45° C.under nitrogen overnight. The mixture was reduced in vacuo to a syrupused directly in the next step. HPLC-MS 279.1 [M+H]⁺, 301.1 [M+Na]⁺,557.2, 579.3 [2M+Na]⁺.

(b) Amine protection. Crude amine (˜0.18 mmol) was dissolved in1,4-dioxan (2.5 mL) with stirring and ice-cooled and a solution ofsodium carbonate (42 mg, 0.37 mmol) in water (2.5 mL) was added.Di-tert-butylcarbonate (46 mg, 0.27 mmol) in 1,4-dioxane (1.0 mL) wasadded dropwise over 30 minutes and the mixture stirred overnight atambient temperature. DCM (20 mL) was then added and the organic phasewashed with 0.1N HCl (20 mL), sat. NaHCO₃ (20 mL), then brine (20 mL)and dried (Na₂SO₄). The organic layer was filtered and reduced in vacuoto leave a clear gum. The crude gum was purified on a 5 g Flash silicacartridge eluting with a gradient of heptane:ethyl acetate 5:1→1:2 toprovide alcohol (37b) as a white foam (65.5 mg) contaminated withtriphenylphosphine oxide. TLC (R_(f)=0.43, EtOAc:heptane 2:1),analytical HPLC R_(t)=15.05 min (product 8.25% by UV) and 15.39 min(triphenylphosphine oxide 91.25% by V), HPLC-MS 279.1 [M+H−Boc]⁺, 323.1[M+2H−Bu]⁺, 401.1 [M+Na]⁺, 557.2, 779.3 [2M+Na]⁺.

(iv) Preparation of (3R,3aR,6S,6aR)-(9H-fluoren-9-yl)methyl6-(tert-butoxycarbonylamino)-3-hydroxytetrahydro-2H-furo[3,2-b]pyrrole-4(5H)-carboxylate(8b). Bicycle alcohol (37b) (60 mg, ˜0.16 mmol) was dissolved inmethanol (5 mL), cooled to 0° C. and 10% palladium on charcoal (15 mg)added. The mixture was stirred, then evacuated and flushed withhydrogen. The mixture was warmed to ambient temperature and after 2 h.filtered through celite. The filter cake was washed with ethanol (3×5mL) and the combined filtrates reduced in vacuo to provide the crudeamine (˜16 mg). HPLC-MS 245.2 [M+H]⁺, 279.1, 511.3 [M+Na]⁺, 557.2. Thecrude amine was dissolved in 1,4-dioxane (2.5 mL) with stirring,ice-cooled and a solution of sodium carbonate (35.5 mg, 0.333 mmol) inwater (2.5 mL) was added. 9-Fluorenylmethyl chloroformate (43 mg, 0.166mmol) in 1,4-dioxane (1.0 mL) was added dropwise over 30 minutes and themixture stirred for a further 1 h. EtOAc (25 mL) was then added and theorganic phase washed with 0.1N HCl (25 mL), sat. NaHCO₃ (25 mL), thenbrine (25 mL) and dried (Na₂SO₄). The organic layer was filtered andreduced in vacuo to leave a clear film (72.5 mg). The crude film waspurified on a 5 g Flash silica cartridge eluting with a gradient ofheptane:ethyl acetate 6:1→3:1 to provide alcohol (8b) as a white solid(40.0 mg) with triphenylphosphine oxide. TLC (R_(f)=0.23, EtOAc:heptane1:1), analytical HPLC 15.39 min (triphenylphosphine oxide 63.8% by UV)and R_(t)=18.30 min (product 33.8% by UV), HPLC-MS 411.2 [M+2H−Bu]⁺,489.2 [M+Na]⁺, 955.4 [2M+Na]⁺ and 279.1, 557.2.

(v) Preparation of (3aS,6S,6aR)-(9H-fluoren-9-yl)methyl6-(tert-butoxycarbonylamino)-3-oxotetrahydro-2H-furo[3,2-b]pyrrole-4(5H)-carboxylate(8c). Bicycle alcohol (8b) (40 mg, ˜0.08 mmol) was dissolved inanhydrous dichloromethane (3 mL) with stirring under argon. Dess-Martinperiodinane (68 mg, 0.16 mmol) was added and the mixture stirredovernight. The mixture was diluted with DCM (20 mL) and washed with sat.NaHCO₃/0.25M Na₂S₂O₃, sat. NaHCO₃, brine (20 mL each) and dried(Na₂SO₄). The organic layer was filtered and reduced in vacuo to leave acolourless gum (˜41 mg). The crude gum was purified on a 5 g Flashsilica cartridge eluting with a gradient of heptane:ethyl acetate5:1→2:1 to provide ketone (8c) as a white solid (17.3 mg, 0.037 mmol).TLC (R_(f)=0.36, EtOAc:heptane 1:1), analytical HPLC broad peak withR_(t)=18.14-20.32 min, HPLC-MS 409.2 [M+2H−Bu]⁺, 465.2 [M+H]⁺, 487.2[M+Na]⁺, 951.4 [2M+Na]⁺; [□]_(D) ²²−67.6° (c=0.74, CHCl₃).

Preparation of (3aS,6R,6aR)-(9H-fluoren-9-yl)methyl6-(tert-butoxycarbonylamino)-3-oxotetrahydro-2H-furo[3,2-b]pyrrole-4(5H)-carboxylate(7c)

(i) Preparation of (3R,3aR,6S,6aS)-Benzyl3-hydroxy-6-(tosyloxy)tetrahydro-2H-furo[3,2-b]pyrrole-4(5H)-carboxylate(34). Ethanol (6 mL) was added dropwise to a mixture of 10% palladium oncharcoal (50 mg) and anti-(33) (547 mg, 1.26 mmol) under an atmosphereof argon. The argon was replaced by hydrogen then the suspension wasstirred at 20° C. for 3.75 hours before filtering the mixture throughcelite in vacuo. The filter cake was washed with ethanol (40 mL) thenthe solvents removed in vacuo from the filtrate to obtain(3R,3aR,6S,6aS)-3-hydroxyhexahydro-2H-furo[3,2-b]pyrrol-6-yl4-methylbenzenesulfonate which was used without further purification.

A solution of sodium carbonate (281 mg, 2.65 mmol) in water (5 mL) wasadded whilst stirring to a solution of(3R,3aR,6S,6aS)-3-hydroxyhexahydro-2H-furo[3,2-b]pyrrol-6-yl4-methylbenzenesulfonate in 1,4-dioxane (5 mL). A solution of benzylchloroformate (0.225 mL, 1.96 mmol) in 1,4-dioxane (2.5 mL) was addedover 20 minutes then the mixture stirred for 35 minutes, then water (50mL) was added and the product extracted into dichloromethane (2×50 mL).The organic layer was washed with brine (50 mL), then dried (Na₂SO₄),filtered and reduced in vacuo to leave a residue. Flash chromatographyover silica, eluting with ethyl acetate:heptane mixtures 25:75 to 50:50gave bicyclic alcohol (34) (518 mg, 95%) as a white solid. TLC(R_(f)=0.25, EtOAc:heptane 3:2), analytical HPLC single main peak,R_(t)=17.86 min., HPLC-MS 434.2 [M+H]⁺, 456.1 [M+Na]⁺, 889.3 [2M+Na]⁺;[□]_(D) ^(16.5)−23.1° (c=1.190, CHCl₃); δ_(H) (500 MHz, CDCl₃) mixtureof rotamers major:minor 3:2; 1.96 (0.4H, d, J=4.11 Hz, OH minor), 2.43(1.8H, s, aryl-CH₃ major), 2.44 (1.2H, s, aryl-CH₃ minor), 2.59 (0.6H,d, J=3.42 Hz, OH major), 3.35 (0.4H, dd, 3.71 Hz, CbzNCH₂ minor), 3.41(0.6H, dd, 3.80 Hz, CbzNCH₂ major), 3.74-3.88 (3H, m, 2×OCH₂CHOH and1×CbzNCH₂), 4.29 (0.4H, s, CbzNCH minor), 4.31 (0.6H, s, CbzNHCH major),4.37 (0.4H, brs, OCH₂CHOH minor), 4.49 (0.6H, brs, OCH₂CHOH major), 4.51(0.6H, d, J=4.59 Hz, TsOCHCH major), 4.64 (0.4H, brd, J=4.44 Hz, TsOCHCHminor), 4.77 (0.4H, d, J=3.43 Hz, TsOCHCH minor), 4.79 (0.6H, d, J=3.53Hz, TsOCHCH major), 5.06-5.13 (1.6H, m, CH₂Ph), 5.21 (0.4H, d, J=12.22Hz, CH₂Ph minor), 7.30 (7H, m, aromatic-CH and CH₃CCH), 7.75-7.79 (2H,m, aromatic OSO₂CCH); δ_(C) (125 MHz, CDCl₃) 21.658 (aryl-CH₃),51.015/51.082 (CbzNCH₂), 67.511/67.622 (CH₂Ph), 67.953/68.902 (CbzNCH),74.375/74.420 (OCH₂CHOH), 75.322/76.156 (OCH₂CHOH), 79.944/80.600(TsOCHCH), 83.537/84.651 (TsOCHCH), 127.791, 127.837, 127.942, 128.011,128.382, 128.485, 128.558, 128.703 and 130.102 (aromatic CH),133.021/133.087 (CHOSO₂C quaternary), 135.895/136.018 (Cbz quaternary),145.441 (CH₃C quaternary), 153.976/154.591 (Cbz C═O).

(ii) Preparation of (3R,3aR,6R,6aS)-benzyl6-azido-3-hydroxytetrahydro-2H-furo[3,2-b]pyrrole-4(5H)-carboxylate(36). Bicycle alcohol (34) (400 mg, 0.93 mmol) was dissolved indimethylformamide (2 mL) in a glass pressure tube and sodium azide (120mg, 1.85 mmol) added. The mixture was sealed and heated at 135° C. withstirring overnight. The viscous dark mixture was reduced in vacuo andthe residue partitioned between DCM (25 mL) and brine (25 mL). Theorganic phase was washed with sat. NaHCO₃ (25 mL), brine (25 mL) anddried (Na₂SO₄). The organic layer was filtered and reduced in vacuo toleave a dark gum (105 mg). The crude gum was partially purified on a 5 gFlash silica cartridge eluting with a gradient of heptane:ethyl acetate8:1→3:1 to provide azidoalcohol (36) as a thick tan oil (77 mg). TLC(R_(f)=0.50, EtOAc:heptane 2:1) plus an unidentified by-product(R_(f)=0.40, EtOAc:heptane 2:1), HPLC-MS277.1 [M+H−N₂]⁺, 305.1 [M+H]⁺,327.1 [M+Na]⁺, 631.2 [2M+Na]⁺.

(iii) Preparation of (3R,3aR,6R,6aR)-benzyl6-(tert-butoxycarbonylamino)-3-hydroxytetrahydro-2H-furo[3,2-b]pyrrole-4(5H)-carboxylate(37).

(a) Reduction of azide. Azide (36) (77 mg, ˜0.25 mmol) was dissolved inTHF (8.5 mL) with stirring and water (46 □L, 2.53 mmol) added followedby triphenylphosphine (99 mg, 0.38 mmol). The mixture was heated at 45°C. under nitrogen overnight. The mixture was reduced in vacuo, theresidue dissolved in DCM (10 mL) and washed with 0.1N HCl (2×5 mL). Theaqueous layer was then adjusted to pH 11 with sat. NaCO₃ and backextracted with DCM (4×10 mL). The combined DCM back extracts were dried(Na₂SO₄), filtered and reduced in vacuo to leave a yellow oil (29.8 mg)used directly in the next step. HPLC-MS 279.1 [M+H]⁺, 301.1 [M+Na]⁺,579.3 [2M+Na]⁺.

(b) Amine protection. Crude amine (29.8 mg, ˜0.11 mmol) was dissolved in1,4-dioxan (1.5 mL) with stirring and ice-cooled and a solution ofsodium carbonate (26 mg, 0.24 mmol) in water (1.5 mL) was added.Di-tert-butylcarbonate (28 mg, 0.16 mmol) in 1,4-dioxane (1.0 mL) wasadded dropwise over 30 minutes and the mixture stirred for a further 1 hat ambient temperature. DCM (20 mL) was then added and the organic phasewashed with 0.1N HCl (20 mL), sat. NaHCO₃ (20 mL), then brine (20 mL)and dried (Na₂SO₄). The organic layer was filtered and reduced in vacuoto leave a clear gum (˜44 mg). The crude gum was purified on a 5 g Flashsilica cartridge eluting with a gradient of heptane:ethyl acetate6:1→1:1 to provide alcohol (37) as a clear gum (30.0 mg, 0.08 mmol, 32%from azide). TLC (R_(f)=0.40, EtOAc:heptane 2:1), analytical HPLCR_(t)=15.25 min, HPLC-MS 279.1 [M+H−Boc]⁺, 323.1 [M+2H−Bu]⁺, 401.1[M+Na]⁺, 779.3 [2M+Na]⁺.

(iv) Preparation of (3R,3aR,6R,6aR)-(9H-fluoren-9-yl)methyl6-(tert-butoxycarbonylamino)-3-hydroxytetrahydro-2H-furo[3,2-b]pyrrole-4(5H)-carboxylate(7b). Bicycle alcohol (37) (30 mg, 0.08 mmol) was dissolved in methanol(3 mL), cooled to 0° C. and 10% palladium on charcoal (10 mg) added. Themixture was stirred, then evacuated and flushed with hydrogen. Themixture was warmed to ambient temperature and after 5 h. filteredthrough celite. The filter cake was washed with ethanol (3×5 mL) and thecombined filtrates reduced in vacuo to provide the crude amine (˜16 mg).HPLC-MS 245.2 [M+H]⁺, 511.3 [M+Na]⁺. The crude amine was dissolved in1,4-dioxane (2.5 mL) with stirring, ice-cooled and a solution of sodiumcarbonate (18 mg, 0.165 mmol) in water (2.5 mL) was added.9-Fluorenylmethyl chloroformate (22 mg, 0.084 mmol) in 1,4-dioxane (1.0mL) was added dropwise over 30 minutes and the mixture stirred for afurther 1 h. DCM (25 mL) was then added and the organic phase washedwith 0.1N HCl (25 mL), sat. NaHCO₃ (25 mL), then brine (25 mL) and dried(Na₂SO₄). The organic layer was filtered and reduced in vacuo to leave aclear film. The crude film was purified on a 5 g Flash silica cartridgeeluting with a gradient of heptane:ethyl acetate 6:1→1:1 to providealcohol (7b) as a white solid (23.4 mg, 0.05 mmol, 63%). TLC(R_(f)=0.46, EtOAc:heptane 2:1), analytical HPLC R_(t)=18.52 min,HPLC-MS 367.2 [M+H−Boc]⁺, 411.2 [M+2H−Bu]⁺, 489.2 [M+Na]⁺, 955.4[2M+Na]⁺; [□]_(D) ¹⁸−17.1° (c=2.34, CHCl₃).

(v) Preparation of (3aS,6R,6aR)-(9H-fluoren-9-yl)methyl6-(tert-butoxycarbonylamino)-3-oxotetrahydro-2H-furo[3,2-b]pyrrole-4(5H)-carboxylate(7c). Bicycle alcohol (7b) (23 mg, 0.05 mmol) was dissolved in anhydrousdichloromethane (3 mL) with stirring under argon. Dess-Martinperiodinane (42 mg, 0.10 mmol) was added and the mixture stirredovernight. Additional Dess-Martin periodinane (21 mg, 0.05 mmol) wasadded and the mixture stirred for a further 2 h. The mixture was dilutedwith DCM (20 mL) and washed with sat. NaHCO₃/0.25M Na₂S₂O₃, sat. NaHCO₃,brine (25 mL each) and dried (Na₂SO₄). The organic layer was filteredand reduced in vacuo to leave a colourless film (˜26 mg). The crude filmwas purified on a 5 g Flash silica cartridge eluting with a gradient ofheptane:ethyl acetate 6:1→2:1 to provide ketone (7c) as a white solid(17.2 mg, 0.037 mmol, 74%). TLC (R_(f)=0.34, EtOAc:heptane 1:1),analytical HPLC broad peak with R_(t)=17.94-20.0 min, HPLC-MS 365.1[M+H-Boc]⁺, 409.1 [M+2H−Bu]⁺, 465.2 [M+H]⁺, 487.2 [M+Na]⁺, 505.2[M+18+Na]⁺, 951.3 [2M+Na]⁺; [□]_(D) ¹⁸−84.3° (c=1.72, CHCl₃); ¹H NMR(500 MHz, CDCl₃ at 300K): δ 1.45 (s, C(CH₃)₃, 9H), 3.05 (t, J=10.40 Hz,FmocNCH₂, 1H), 4.01 (d, J=16.90 Hz, OCH₂C(O), 1H), 4.03-4.08 (b,FmocNCH₂, 0.4H), 4.15-4.65 (bm,FmocNCH₂+FmocCH+OCH₂C(O)+NCHC(O)+FmocCH₂, 5.6H), 4.75 (b, BocNHCHCHO,1H), 5.07 (b, BocNHCH, 1H), 7.32 (dt, J=0.95, 8.4 Hz, Fmoc H-2 and H-7),7.39 (t, J=7.50 Hz, Fmoc H-3 and H-6), 7.56 (bd, J=6.2 Hz, 1.0 Fmoc H-1or H-8), 7.65 (bd, J=6.6 Hz, 0.25 Fmoc H-1 or H-8), 7.73-7.77 (d+m,J=7.40 Hz, Fmoc H-4 and H-5+0.75H-1 or H-8); ¹³C NMR (125 MHz, CDCl₃ at300K): δ 28.30 (C(CH₃)₃), 47.17 (FmocCH₂), 48.21/48.36 (FmocNCH₂),51.83/52.35 (CHNHBoc), 60.95/61.31 (NCHC(O)), 68.00/68.33 (FmocCH₂),70.66 (OCH₂C(O)), 80.32/81.12 (BocNHCHCHO), 119.91/120.02 (Fmoc C-4 andC-5), 124.95/125.01/125.13/125.36 (Fmoc C-1 and C-8), 127.10 (Fmoc C-2and C-7), 127.75 (Fmoc C-3 and C-6), 141.27/141.33/143.52/143.69/144.30(Fmoc quaternary aromatics), 154.37/154.66/155.10(FmOC(O)N+Bu^(t)OC(O)NH), 207.31/207.45 (C═O).

Preparation of (3R,3aR,6S,6aS)-tert-butyl3-hydroxy-6-(methylthio)tetrahydro-2H-furo[3,2-b]pyrrole-4(5H)-carboxylate(54)

A stirred solution of tosylate (35b) (250 mg, 0.63 mmol) and sodiumthiomethoxide [CAS 5188-07-8] (88 mg, 1.25 mmol) in 3 ml of DMA washeated under an atmosphere of argon in a sealed pressure vessel at 90°C. for 2 hours. The mixture was then allowed to cool to ambienttemperature then an aqueous saturated solution of ammonium chloride (10mL) was added. The aqueous phase was extracted with tert-butyl methylether (3×7 ml). The organic phase was dried (MgSO₄), filtered andreduced in vacuo to leave an oil. Flash chromatography over silica,eluting with diethyl ether:pentane 2:1 gave thiomethylether (54) ascolourless oil (0.152 g, 88%). TLC (R_(f)=0.29, Et₂O:pentane 2:1),HPLC-MS 220.1 [M+2H−^(t)Bu]⁺, 573.2 [2M+H]⁺; δ_(H) (500 MHz, CDCl₃)mixture of rotamers 1:1; 1.46 (4.5H, s, CCH₃), 1.49 (4.5H, s, CCH₃),2.16 (3H, s, SCH₃), 3.20 (1H, brs, BocNCH₂), 3.47-4.05 (4H, m, OCH₂CHOH,BocNCH₂ and CHSCH₃), 4.24-4.45 (2H, m, BocNCH and OCH₂CHOH), 4.63 (1H,s, OCHCHSCH₃).

Preparation of (3R,3aR,6S,6aS)-(9H-fluoren-9-yl)methyl3-hydroxy-6-(methylthio)tetrahydro-2H-furo[3,2-b]pyrrole-4(5H)-carboxylate(55)

A solution of HCl in 1,4-dioxane (4M, 5.5 mL) was added tothiomethylether (54) (152 mg, 0.55 mmol). The mixture stirred for 1 hourthen the solvents removed in vacuo. The residue was azeotroped withCH₃CN (5 mL) to obtain(3R,3aR,6S,6aS)-6-(methylthio)hexahydro-2H-furo[3,2-b]pyrrol-3-ol whichwas used without further purification.

A solution of(3R,3aR,6S,6aS)-6-(methylthio)hexahydro-2H-furo[3,2-b]pyrrol-3-ol in1,4-dioxane (5 mL) was added whilst stirring to a solution of sodiumcarbonate (123 mg, 1.16 mmol) in water (1.5 mL) at 0° C. A solution of9-fluorenylmethoxycarbonyl chloride (150 mg, 0.58 mmol) in 1,4-dioxane(1.5 mL) was added dropwise over 5 minutes then the mixture allowed towarm to ambient temperature over 2 hours. Water (20 mL) was added andthe product extracted into dichloromethane (3×10 mL). The organic layerwas dried (Na₂SO₄), filtered and reduced in vacuo to leave a residue.Flash chromatography over silica, eluting with diethyl ether:pentanemixtures 2:1 gave alcohol (55) as a white solid (130 mg, 60%). TLC(R_(f)=0.19, Et₂O:pentane 2:1); HPLC-MS 398.2 [M+H]⁺, 420.1 [M+Na]⁺,817.3 [2M+H]⁺; analytical HPLC single main peak, R_(t)=16.096 min.,[□]_(D) ¹⁷−59.4° (c=2.78, CHCl₃); δ_(H) (500 MHz, CDCl₃) mixture ofrotamers major:minor 4:3; 1.06 (0.57H, d, J=3.63 Hz, OH major), 2.04(1.71H, s, SCH₃ major), 2.14 (1.29H, s, SCH₃ minor), 2.57 (0.43H, d,J=2.83 Hz, OH minor), 3.10 (0.57H, d, J=5.40 Hz, FmocNCH₂ major),3.21-3.24 (0.43H, m, FmocNCH₂ minor), 3.41 (0.57H, dd, 5.57 Hz, OCH₂CHOHmajor), 3.52-3.82 (4.43H, m, FmocNCH, CHSCH₃ OCH₂CHOH minor, 1×FmocNCH₂and 1×OCH₂CHOH), 3.92 (0.43H, dd, 4.41 Hz, OCH₂CHOH minor), 4.23-4.84(4.57H, m, Fmoc CH, OCHCHSCH₃, Fmoc CH₂ minor and 1×OCH₂CHOH major),7.28-7.80 (8H, Fmoc aromatic CH); δ_(C) (125 MHz, CDCl₃) 14.574/14.768(SCH₃), 47.234, 47.445, 48.069 and 48.826 (Fmoc CH and CHSCH₃),50.417/50.633 (FmocNCH₂), 65.752/67.282 (Fmoc CH₂), 68.555/69.282(FmocNCH), 74.361/74.600 (OCH₂CHOH), 75.774/76.148 (OCH₂CHOH),85.505/86.026 (OCHCHOCH₃), 119.848, 120.003, 120.029, 124.512, 124.593,124.946, 127.030, 127.063, 127.427, 127.507, 127.755, 127.771 and127.892 (Fmoc aromatic CH), 141.196, 141.320, 141.378, 141.428, 143.581,143.818, 143.890 and 143.964 (Fmoc quaternary), 154.115/154.849 (FmocC═O).

Preparation of (3aS,6S,6aS)-(9H-Fluoren-9-yl)methyl6-(methylthio)-3-oxotetrahydro-2H-furo[3,2-b]pyrrole-4(5H)-carboxylate(56)

Dess-Martin periodinane (130 mg, 0.65 mmol) was added to a stirredsolution of alcohol (55) (278 mg, 0.33 mmol) in dichloromethane (10 mL)under an atmosphere of argon. The mixture was stirred for 1 hour thendiluted with dichloromethane (25 mL). The organic phase was washed witha mixture of saturated aqueous sodium bicarbonate and 10% aqueous sodiumthiosulphate solution (1:1, 20 mL), then dried (Na₂SO₄), filtered andreduced in vacuo. Flash chromatography over silica, eluting with diethylether:pentane mixtures 60:40 to 65:35 gave ketone (56) (113 mg, 87%) asa white solid. TLC (R_(f)=0.24, Et₂O:pentane 2:1); analytical HPLC twomain peaks, R_(t)=15.71 and 15.91 min.; HPLC-MS 396.1 [M+H]⁺, 414.1[M+H₂O+Na]⁺, 813.2 [2M+H]⁺; [□]_(D) ¹⁸−137.3° (c=2.33, CHCl₃). δ_(H)(500 MHz, CDCl₃) mixture of rotamers approx. 1:1; 2.15 (1.5H, s, SCH₃),2.19 (1.5H, s, SCH₃), 3.30-3.38 (1H, m, CHSMe), 3.68-3.80 (1.5H, m,FmocNCH₂), 3.93-4.05 (1.5H, m, 0.5×FmocNCH₂ and OCH₂C═O), 4.10-4.35(2.5H, m, OCH₂C═O, Fmoc-CH, and 0.5×Fmoc-CH₂), 4.40-4.54 (2.5H, m1.5×Fmoc-CH₂ and FmocNCH), 4.74-4.84 (1H, m, OCHCHSCH₃), 7.28-7.77 (8H,Fmoc aromatic CH); δ_(C) (125 MHz, CDCl₃); 14.662 (SCH₃), 47.133(Fmoc-CH), 48.449/48.954 (CHSCH₃), 50.539/53.419 (FmocNCH₂),61.005/61.420 (FmocNCH), 67.710/68.437 (Fmoc-CH₂), 70.733 (OCH₂C═O),85.174/86.042 (OCHCHSCH₃), 119.916, 119.987, 124.917, 124.964, 125.240,125.448, 127.069, 127.712 and 127.969 (Fmoc aromatic CH),141.255/141.317, 143.627, 143.778 and 144.264 (Fmoc quaternary),154.942/155.049 (Fmoc C═O), 207.818/207.973 (ketone C═O).

Preparation of (3R,3aR,6S,6aR)-benzyl3-hydroxy-6-(methylamino)tetrahydro-2H-furo[3,2-b]pyrrole-4(5H)-carboxylate(57)

A stirred solution of tosylate (34b) (200 mg, 0.46 mmol) and methylaminein ethanol (33% wt, 6 mL) was heated in a sealed pressure vessel at 150°C. for 72 hours. The mixture was then allowed to cool to ambienttemperature then solvents removed in vacuo. The residue was dissolved indichloromethane (20 mL), washed with water (15 mL) then dried (Na₂SO₄),filtered and reduced in vacuo. Flash chromatography over silica, elutingwith dichloromethane:methanol mixtures 97:3 to 95:5 gavemethylaminoalcohol (57) as a pale yellow solid (47 mg, 35%). TLC(R_(f)=0.22, DCM:MeOH 93:7), HPLC-MS 293.1 [M+H]⁺, 315.2 [M+Na]⁺, 607.3[2M+Na]⁺; δ_(H) (500 MHz, CDCl₃) mixture of rotamers major:minor 3:2;2.42 (1.8H, s, NHCH₃ major), 2.3 (1.2H, s, NHCH₃ minor), 3.14-3.16 (1H,m, CHNHCH₃), 3.35-4.48 (7H, m, OCH₂CHOH, CHCHCHCH₂NCbz), 5.06 and 5.22(0.8H total, each d, J=12.22 Hz, Cbz minor), 5.12 (1.2H, s, Cbz major),7.27-7.37 (5H, m, aromatic CH).

Preparation of (3R,3aR,6S,6aR)-benzyl6-(tert-butoxycarbonyl(methyl)amino)-3-hydroxytetrahydro-2H-furo[3,2-b]pyrrole-4(5H)-carboxylate(58)

A solution of di-tert-butyl dicarbonate (48 mg, 0.22 mmol) anddiisopropyl ethyl amine (30 mg, 0.23 mmol) in dichloromethane (1.5 mL)was added dropwise over 5 minutes to a solution of methylaminoalcohol(57) (47 mg, 0.161 mmol) dichloromethane (1.5 mL). The mixture wasstirred for 16 hours then diluted with dichloromethane (10 mL), thenwashed with hydrochloric acid (1M, 5 mL), reduced in vacuo to leave Bocalcohol (58) as a yellow oil (72 mg). TLC (R_(f)=0.41, Et₂O), HPLC-MS293.1 [M−Boc+H]⁺, 337.1 [M+2H−^(t)Bu]⁺, 415.2 [M+Na]⁺, 807.3 [2M+Na]⁺.

Preparation of (3R,3aR,6S,6aS)-tert-butyl6-ethoxy-3-hydroxytetrahydro-2H-furo[3,2-b]pyrrole-4(5H)-carboxylate(59)

A stirred mixture of tosylate (35b) (20 mg, 0.05 mmol), ethanol (1 mL)and sodium ethoxide solution in ethanol (21% wt, 94 μL, 0.25 mmol) washeated under an atmosphere of argon at 80° C. for 16 hours. The mixturewas diluted with aqueous saturated sodium hydrogen carbonate solution(10 mL) then extracted with tert-butyl methyl ether (3×5 mL). Theorganic phase was dried (MgSO₄), filtered and reduced in vacuo to leavean oil. Flash chromatography over silica, eluting with diethylether:pentane mixtures 65:35 to 83:17 gave ethoxyalcohol (59) as a paleyellow solid (1 mg, 7%). TLC (R_(f)=0.50, Et₂O); analytical HPLC mainpeak, R_(t)=15.35 min., HPLC-MS 218.1 [M+2H−^(t)Bu]⁺, 296.1 [M+Na]⁺,569.3 [2M+Na]⁺.

Preparation of 4-(4-cyclobutylpiperazin-1-yl)benzoic Acid (64)

(i) Methyl 4-(piperazin-1-yl)benzoate (CAS 163210-97-7, 500 mg, 2.27mmol) was dissolved in THF (10 mL) and water (0.2 mL) with stirring.Cyclobutanone (0.238 g, 3.4 mmol) was added followed by acetic acid (0.5mL) and sodium cyanoborohydride (0.211 g, 3.4 mmol). The mixture wasrefluxed for 6 h, cooled and reduced in vacuo. The residue was dissolvedin 1N HCl (3 mL) and water (12 mL) then washed with ethyl acetate (2×10mL). The aqueous layer was adjusted to pH 10 with potassium carbonateand extracted with ethyl acetate (3×10 mL). The combined organics weredried (MgSO₄), filtered and reduced in vacuo to give crude methyl ester(0.56 g).

(ii) Methyl ester (0.51 g, assume 1.85 mmol) was suspended in 10% NaOH(3 mL) and water (3 mL) added. The mixture was heated at 80° C. for 2 h,then cooled to 0° C. The mixture was acidified to pH 2 with 6N HCl, thencooled for 2 h at −5° C. A tan solid was filtered and washed thoroughlywith hexane and dried in vacuo to give acid (64) (yield 0.25 g). HPLC-MS261 [M+H]⁺.

Preparation of 4-(1-ethylpiperidin-4-yl)benzoic Acid (65)

(i) Methyl 4-(piperidin-4-yl)benzoate (CAS 281235-04-9, 1.0 g, 4.6mmol), DIPEA (0.653 g, 5.07 mmol) and ethyl bromide (0.516 mL, 6.9 mmol)were dissolved in 1,2-dimethoxyethane (18 mL) and refluxed at 78° C.overnight. The mixture was cooled, reduced in vacuo and the residue waspartitioned between ethyl acetate and aq. sodium carbonate. The aqueousphase was extracted twice with ethyl acetate and the combined organicswere dried (MgSO₄), filtered and reduced in vacuo to give crude methylester. The crude ester was purified over silica gel eluting withCHCl₃:MeOH (97.5:2.5 v/v).

(ii) Methyl ester (0.51 g, assume 2.05 mmol) was suspended in 10% NaOH(3 mL) and water (3 mL) added. The mixture was heated at 80° C. for 2 h,then cooled to 0° C. The mixture was acidified to pH 2 with 6N HCl, thencooled for 2 h at −5° C. A solid was filtered and washed thoroughly withhexane and dried in vacuo to give acid (65) (yield 0.25 g).

Preparation of 4-(1-cyclopropylpiperidin-4-yl)benzoic Acid (66)

(i) Methyl 4-(piperidin-4-yl)benzoate (CAS 281235-04-9, 0.5 g, 2.27mmol) was dissolved in a mixture of THF (10 mL) and MeOH (10 mL). Aceticacid (1.38 g, 22.7 mmol) and [(1-ethoxycyclopropyl)oxy]trimethylsilane(0.8 g, 4.6 mmol) were added followed by sodium cyanoborohydride (0.433g, 6.9 mmol). The mixture was stirred for 7 h then reduced in vacuo. Theresidue was dissolved in 1N HCl (3 mL) and water (12 mL) then washedwith ethyl acetate (2×10 mL). The aqueous layer was adjusted to pH 10with potassium carbonate and extracted with ethyl acetate (3×10 mL). Thecombined organics were washed with brine then dried (MgSO₄), filteredand reduced in vacuo to give crude methyl ester (0.35 g). The crudeester was purified over silica gel eluting with hexane:ethyl acetate(85:15 v/v).

(ii) Methyl ester (0.20 g, assume 0.77 mmol) was suspended in 10% NaOH(2.5 mL) and water (2.5 mL) added. The mixture was heated at 80° C. for2 h, then cooled to 0° C. The mixture was acidified to pH 2 with 6N HCl,then cooled for 2 h at −5° C. A solid was filtered and washed thoroughlywith hexane and dried in vacuo to give acid (66) (yield 0.04 g).

Preparation of 4-(1-cyclobutylpiperidin-4-yl)benzoic Acid (67)

(i) Methyl 4-(piperidin-4-yl)benzoate (CAS 281235-04-9, 0.25 g, 1.13mmol) was dissolved in a mixture of THF (6 mL) and water (0.1 mL).Acetic acid (0.25 mL) and cyclobutanone (0.119 g, 1.7 mmol) were addedfollowed by sodium cyanoborohydride (0.15 g, 2.4 mmol). The mixture wasrefluxed for 5 h then cooled and reduced in vacuo. The residue wasdissolved in 1N HCl (4 mL) and water (15 mL) then washed with ethylacetate (2×10 mL). The aqueous layer was adjusted to pH 10 withpotassium carbonate and extracted with ethyl acetate (3×10 mL). Thecombined organics were washed with brine then dried (MgSO₄), filteredand reduced in vacuo to give crude methyl ester (0.23 g).

(ii) Methyl ester (0.23 g, assume 0.84 mmol) was suspended in 10% NaOH(2.5 mL) and water (2.5 mL) added. The mixture was heated at 80° C. for2 h, then cooled to 0° C. The mixture was acidified to pH 2 with 6N HCl,then cooled for 2 h at −5° C. A solid was filtered and washed thoroughlywith hexane and dried in vacuo to give acid (67) (yield 0.1 g).

Solid Phase Chemistry

Fmoc-ketone building blocks (3c-8c, 56) were utilised in a solid phasesynthesis of example inhibitors (1-79) of general formula I. The methodsused were directly analogous to those described in detail in WO02057270,utilising the 4-{[(Hydrazinocarbonyl)amino]methyl}cyclohexane carboxylicacid trifluoroacetate based linker, solid phase lanterns (ex Mimotopes),standard Fmoc chemistries and acidolytic cleavage followed bysemi-preparative HPLC purification (see WO02057270 pg 124-127 for fullgeneric details). Alternative EXAMPLES of the invention can readily beprepared by the general methods detailed in WO02057270 through use ofthe appropriately derivatised 4-(4-alkylpiperazin-1-yl)benzoic acid or4-(1-alkylpiperidin-4-yl)benzoic acid building block (general syntheticdetails for preparation are given in WO0158886) such as4-(4-methylpiperazin-1-yl)benzoic acid (CAS 354813-15-3),4-(4-ethylpiperazin-1-yl)benzoic acid (CAS 354813-18-6),4-(4-propylpiperazin-1-yl)benzoic acid (CAS 354813-21-1),4-(4-isopropylpiperazin-1-yl)benzoic acid (CAS 354813-24-4),4-(4-(2-methoxyethyl)piperazin-1-yl)benzoic acid (CAS 354813-30-2),4-(4-cyclopropylpiperazin-1-yl)benzoic acid (CAS 883743-83-7),4-(1-methylpiperidin-4-yl)benzoic acid (CAS 35481349-3),4-(1-propylpiperidin-4-yl)benzoic acid (CAS 354813-33-5),4-(1-isopropylpiperidin-4-yl)benzoic acid (CAS 35481342-6),4-(1-(2-methoxyethyl)piperidin-4-yl)benzoic acid (CAS 354813-38-0).Additional novel preferred carboxylic acids are prepared by simpleadaptation of the general methods detailed in WO01058886.

Example 1N—((S)-1-((3aS,6S,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)-4-(4-methylpiperazin-1-yl)benzamide

HPLC-MS R_(t)=2.96 min, 473.3 [M+H]⁺, 491.3 [M+H+18]⁺.

Example 2N—((S)-1-((3aS,6S,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)-4-(4-methylpiperazin-1-yl)benzamide

HPLC-MS R_(t)=3.26 min, 487.3 [M+H]⁺, 505.3 [M+H+18]⁺.

Example 3N—((S)-1-((3aS,6R,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)-4-(4-methylpiperazin-1-yl)benzamide

HPLC-MS R_(t)=2.83 min, 473.2 [M+H]⁺, 491.2 [M+H+18]⁺.

Example 4N—((S)-1-((3aS,6R,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)-4-(4-methylpiperazin-1-yl)benzamide

HPLC-MS R_(t)=3.05 min, 487.3 [M+H]⁺, 505.3 [M+H+18]⁺.

Example 54-(4-ethylpiperazin-1-yl)-N—((S)-1-((3aS,6S,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)benzamide

HPLC-MS R_(t)=3.06 min, 487.3 [M+H]⁺, 505.3 [M+H+18]⁺.

Example 64-(4-ethylpiperazin-1-yl)-N—((S)-1-((3aS,6S,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4dimethyl-1-oxopentan-2-yl)benzamide

HPLC-MS R_(t)=3.36 min, 501.3 [M+H]⁺, 519.3 [M+H+18]⁺.

Example 74-(4-ethylpiperazin-1-yl)-N—((S)-1-((3aS,6R,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)benzamide

HPLC-MS R_(t)=2.85 min, 487.3 [M+H]⁺, 505.3 [M+H+18]⁺.

Example 84-(4-ethylpiperazin-1-yl)-N—((S)-1-((3aS,6R,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)benzamide

HPLC-MS R_(t)=3.18 min, 501.3 [M+H]⁺, 519.3 [M+H+18]⁺.

Example 9N—((S)-1-((3aS,6S,6aR)-6-amino-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)-4-(4-propylpiperazin-1-yl)benzamide

HPLC-MS R_(t)=2.37 min, 486.4 [M+H]⁺, 504.4 [M+H+18]⁺.

Example 10N—((S)-1-((3aS,6R,6aR)-6-amino-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)-4-(4-propylpiperazin-1-yl)benzamide

HPLC-MS R_(t)=2.37 min, 486.4 [M+H]⁺.

Example 11N—((S)-1-((3aS,6S,6aS)-6-hydroxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)-4-(4-propylpiperazin-1-yl)benzamide

HPLC-MS R_(t)=2.85 min, 487.3 [M+H]⁺, 505.3 [M+H+18]⁺.

Example 12N—((S)-1-((3aS,6R,6aS)-6-hydroxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)-4-(4-propylpiperazin-1-yl)benzamide

HPLC-MS R_(t)=2.71 min, 487.4 [M+H]⁺, 505.4 [M+H+18]⁺.

Example 13N—((S)-1-((3aS,6S,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)-4-(4-propylpiperazin-1-yl)benzamide

HPLC-MS R_(t)=3.27 min, 501.3 [M+H]⁺, 519.3 [M+H+18]⁺.

Example 14N—((S)-1-((3aS,6S,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)-4-(4-propylpiperazin-1-yl)benzamide

HPLC-MS R_(t)=3.58 min, 515.3 [M+H]⁺, 533.3 [M+H+18]⁺.

Example 15N—((S)-1-((3aS,6R,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)-4-(4-propylpiperazin-1-yl)benzamide

HPLC-MS R_(t)=3.24 min, 501.3 [M+H]⁺, 519.3 [M+H+18]⁺.

Example 16N—((S)-1-((3aS,6R,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)-4-(4-propylpiperazin-1-yl)benzamide

HPLC-MS R_(t)=3.39 min, 515.3 [M+H]⁺, 533.3 [M+H+18]⁺.

Example 174-(4-isopropylpiperazin-1-yl)-N—((S)-1-((3aS,6S,6aR)-6-amino-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)benzamide

HPLC-MS R_(t)=2.61 min, 500.4 [M+H]⁺, 518.4 [M+H+18]⁺.

Example 184-(4-isopropylpiperazin-1-yl)-N—((S)-1-((3aS,6R,6aR)-6-amino-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)benzamide

HPLC-MS R_(t)=2.64 min, 500.4 [M+H]⁺.

Example 194-(4-isopropylpiperazin-1-yl)-N—((S)-1-((3aS,6S,6aS)-6-hydroxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)benzamide

HPLC-MS R_(t)=3.05 min, 501.4 [M+H]⁺, 519.4 [M+H+18]⁺.

Example 204-(4-isopropylpiperazin-1-yl)-N—((S)-1-((3aS,6R,6aS)-6-hydroxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)benzamide

HPLC-MS R_(t)=2.98 min, 501.4 [M+H]⁺, 519.4 [M+H+18]⁺.

Example 214-(4-isopropylpiperazin-1-yl)-N—((S)-1-((3aS,6S,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)benzamide

HPLC-MS R_(t)=3.53 min, 515.4 [M+H]⁺, 533.4 [M+H+18]⁺.

Example 224-(4-isopropylpiperazin-1-yl)-N—((S)-1-((3aS,6R,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)benzamide

HPLC-MS R_(t)=3.32 min, 515.3 [M+H]⁺, 533.3 [M+H+18]⁺.

Example 23N—((S)-1-((3aS,6S,6aR)-6-amino-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)-4-(4-(2-methoxyethyl)piperazin-1-yl)benzamide

HPLC-MS R_(t)=2.14 min, 502.3 [M+H]⁺, 520.3 [M+H+18]⁺.

Example 24N—((S)-1-((3aS,6R,6aR)-6-amino-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)-4-(4-(2-methoxyethyl)piperazin-1-yl)benzamide

HPLC-MS R_(t)=2.12 min, 502.3 [M+H]⁺.

Example 25N—((S)-1-((3aS,6S,6aS)-6-hydroxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)-4-(4-(2-methoxyethyl)piperazin-1-yl)benzamide

HPLC-MS R_(t)=2.83 min, 503.3 [M+H]⁺, 521.3 [M+H+18]⁺.

Example 26N—((S)-1-((3aS,6R,6aS)-6-hydroxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)-4-(4-(2-methoxyethyl)piperazin-1-yl)benzamide

HPLC-MS R_(t)=2.59 min, 503.3 [M+H]⁺, 521.3 [M+H+18]⁺.

Example 27N—((S)-1-((3aS,6S,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)-4-(4-(2-methoxyethyl)piperazin-1-yl)benzamide

HPLC-MS R_(t)=3.16 min, 517.3 [M+H]⁺, 535.3 [M+H+18]⁺.

Example 28N—((S)-1-((3aS,6R,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)-4-(4-(2-methoxyethyl)piperazin-1-yl)benzamide

HPLC-MS R_(t)=2.96 min, 517.3 [M+H]⁺, 535.3 [M+H+18]⁺.

Example 29 4-(4-cyclopropylpiperazin-1-yl)-N—((S)-1-((3aS,6S,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)benzamide

HPLC-MS R_(t)=3.19 min, 499.4 [M+H]⁺, 517.4 [M+H+18]⁺.

Example 304-(4-cyclopropylpiperazin-1-yl)-N—((S)-1-((3aS,6S,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)benzamide

HPLC-MS R_(t)=3.50 min, 513.4 [M+H]⁺, 531.4 [M+H+18]⁺.

Example 314-(4-cyclopropylpiperazin-1-yl)-N—((S)-1-((3aS,6R,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)benzamide

HPLC-MS R_(t)=2.95 min, 499.4 [M+H]⁺, 517.4 [M+H+18]⁺.

Example 324-(4-cyclopropylpiperazin-1-yl)-N—((S)-1-((3aS,6R,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)benzamide

HPLC-MS R_(t)=3.31 min, 513.4 [M+H]⁺, 531.4 [M+H+18]⁺.

Example 33N—((S)-1-((3aS,6S,6aR)-6-amino-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)-4-(1-propylpiperidin-4-yl)benzamide

HPLC-MS R_(t)=2.87 min, 499.4 [M+H]⁺, 517.4 [M+H+18]⁺.

Example 34N—((S)-1-((3aS,6R,6aR)-6-amino-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)-4-(1-propylpiperidin-4-yl)benzamide

HPLC-MS R_(t)=2.91 min, 499.4 [M+H]⁺, 517.4 [M+H+18]⁺.

Example 35N—((S)-1-((3aS,6S,6aS)-6-hydroxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)-4-(1-propylpiperidin-4-yl)benzamide

HPLC-MS R_(t)=3.32 min, 500.4 [M+H]⁺, 518.4 [M+H+18]⁺.

Example 36N—((S)-1-((3aS,6R,6aS)-6-hydroxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)-4-(1-propylpiperidin-4-yl)benzamide

HPLC-MS R_(t)=3.25 min, 500.4 [M+H]⁺, 518.4 [M+H+18]⁺.

Example 37N—((S)-1-((3aS,6S,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)-4-(1-propylpiperidin-4-yl)benzamide

HPLC-MS R_(t)=3.48 min, 500.3 [M+H]⁺, 518.3 [M+H+18]⁺.

Example 38N—((S)-1-((3aS,6R,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)-4-(1-propylpiperidin-4-yl)benzamide

HPLC-MS R_(t)=3.58 min, 514.3 [M+H]⁺, 532.3 [M+H+18]⁺.

Example 39N—((S)-1-((3aS,6S,6aR)-6-amino-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)-4-(1-(2-methoxyethyl)piperidin-4-yl)benzamide

HPLC-MS R_(t)=2.44 min, 501.4 [M+H]⁺, 519.4 [M+H+18]⁺.

Example 40N—((S)-1-((3aS,6R,6aR)-6-amino-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)-4-(1-(2-methoxyethyl)piperidin-4-yl)benzamide

HPLC-MS R_(t)=2.45 min, 501.4 [M+H]⁺, 519.4 [M+H+18]⁺.

Example 41N—((S)-1-((3aS,6S,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)-4-(1-propylpiperidin-4-yl)benzamide

HPLC-MS R_(t)=3.82 min, 514.3 [M+H]⁺, 532.3 [M+H+18]⁺.

Example 42N—((S)-1-((3aS,6R,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)-4-(1-propylpiperidin-4-yl)benzamide

HPLC-MS R_(t)=3.27 min, 500.3 [M+H]⁺, 518.3 [M+H+18]⁺.

Example 43N—((S)-1-((3aS,6S,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)-4-(1-(2-methoxyethyl)piperidin-4-yl)benzamide

HPLC-MS R_(t)=2.86 min, 516.4 [M+H]⁺, 534.4 [M+H+18]⁺.

Example 44N—((S)-1-((3aS,6R,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)-4-(1-(2-methoxyethyl)piperidin-4-yl)benzamide

HPLC-MS R_(t)=2.77 min, 516.4 [M+H]⁺, 534.4 [M+H+18]⁺.

Example 454-(1-cyclopropylpiperidin-4-yl)-N—((S)-1-((3aS,6S,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)benzamide

HPLC-MS R_(t)=3.40 min, 498.4 [M+H]⁺, 516.4 [M+H+18]⁺.

Example 464-(1-cyclopropylpiperidin-4-yl)-N—((S)-1-((3aS,6S,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)benzamide

HPLC-MS R_(t)=3.76 min, 512.4 [M+H]⁺, 530.4 [M+H+18]⁺.

Example 47N—((S)-1-((3aS,6S,6aS)-6-hydroxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)-4-(1-(2-methoxyethyl)piperidin-4-yl)benzamide

HPLC-MS R_(t)=3.28 min, 502.4 [M+H]⁺, 520.4 [M+H+18]⁺.

Example 48N—((S)-1-((3aS,6R,6aS)-6-hydroxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)-4-(1-(2-methoxyethyl)piperidin-4-yl)benzamide

HPLC-MS R_(t)=3.14 min, 502.4 [M+H]⁺, 520.4 [M+H+18]⁺.

Example 494-(1-cyclopropylpiperidin-4-yl)-N—((S)-1-((3aS,6R,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)benzamide

HPLC-MS R_(t)=3.17 min, 498.4 [M+H]⁺, 516.4 [M+H+18]⁺.

Example 504-(1-cyclopropylpiperidin-4-yl)-N—((S)-1-((3aS,6R,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)benzamide

HPLC-MS R_(t)=3.49 min, 512.4 [M+H]⁺, 530.4 [M+H+18]⁺.

Example 51N—((S)-1-((3aS,6S,6aS)-6-hydroxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxobutan-2-yl)-4-(4-methylpiperazin-1-yl)benzamide

HPLC-MS R_(t)=2.52 min, 459.2 [M+H]⁺, 477.2 [M+H+18]⁺.

Example 52N-((2S,3S)-1-((3aS,6S,6aS)-6-hydroxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)-4-(4-methylpiperazin-1-yl)benzamide

HPLC-MS R_(t)=2.62 min, 459.2 [M+H]⁺, 477.2 [M+H+18]⁺.

Example 53N—((S)-1-cyclohexyl-2-((3aS,6S,6aS)-6-hydroxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-methylpiperazin-1-yl)benzamide

HPLC-MS R_(t)=3.12 min, 485.2 [M+H]⁺, 503.3 [M+H+18]⁺, 991.4 [2M+Na]⁺.

Example 54N—((S)-1-cyclopentyl-2-((3aS,6S,6aS)-6-hydroxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-methylpiperazin-1-yl)benzamide

HPLC-MS R_(t)=2.77 min, 471.2 [M+H]⁺, 489.2 [M+H+18]⁺.

Example 55N—((S)-1-cyclopentyl-2-((3aS,6S,6aS)-6-hydroxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-propylpiperazin-1-yl)benzamide

HPLC-MS R_(t)=3.08 min, [499.3 M+H]⁺, 517.3 [M+H+18]⁺.

Example 56N—((S)-1-cyclopentyl-2-((3aS,6S,6aS)-6-hydroxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(1-propylpiperidin-4-yl)benzamide

HPLC-MS R_(t)=3.27 min, 498.3 [M+H]⁺, 516.3 [M+H+18]⁺.

Example 57N—((S)-1-((3aS,6S,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxobutan-2-yl)-4-(4-methylpiperazin-1-yl)benzamide

HPLC-MS R_(t)=2.83 min, 473.2 [M+H]⁺, 491.2 [M+H+18]⁺.

Example 58N-((2S,3S)-1-((3aS,6S,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)-4-(4-methylpiperazin-1-yl)benzamide

HPLC-MS R_(t)=2.93 min, 473.2 [M+H]⁺, 491.3 [M+H+18]⁺, 967.5 [2M+Na]⁺.

Example 59N—((S)-1-cyclohexyl-2-((3aS,6S,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-methylpiperazin-1-yl)benzamide

HPLC-MS R_(t)=3.40 min, 499.3 [M+H]⁺, 517.3 [M+H+18]⁺, 1019.4 [2M+Na]⁺.

Example 60N—((S)-1-cyclopentyl-2-((3aS,6S,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-methylpiperazin-1-yl)benzamide

HPLC-MS R_(t)=3.08 min, 485.3 [M+H]⁺, 503.3 [M+H+18]⁺, 991.5 [2M+Na]⁺.

Example 61N—((S)-1-cyclopentyl-2-((3aS,6S,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-ethylpiperazin-1-yl)benzamide

HPLC-MS R_(t)=3.17 min, [499.3 M+H]⁺, 517.3 [M+H+18]⁺.

Example 62N—((S)-1-cyclopentyl-2-((3aS,6S,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-propylpiperazin-1-yl)benzamide

HPLC-MS R_(t)=3.38 min, 513.3 [M+H]⁺, 531.3 [M+H+18]⁺, 1047.4 [2M+Na]⁺.

Example 63N—((S)-1-cyclopentyl-2-((3aS,6S,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-isopropylpiperazin-1-yl)benzamide

HPLC-MS R_(t)=3.31 min, 513.3 [M+H]⁺, 531.3 [M+H+18]⁺, 1047.4 [2M+Na]⁺.

Example 64N—((S)-1-cyclopentyl-2-((3aS,6S,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-(2-methoxyethyl)piperazin-1-yl)benzamide

HPLC-MS R_(t)=3.26 min, 529.3 [M+H]⁺, 547.3 [M+H+18]⁺, 1079.4 [2M+Na]⁺.

Example 65N—((S)-1-cyclopentyl-2-((3aS,6S,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-cyclopropylpiperazin-1-yl)benzamide

HPLC-MS R_(t)=3.25 min, 511.3 [M+H]⁺, 529.3 [M+H+18]⁺.

Example 664-(4-cyclobutylpiperazin-1-yl)-N—((S)-1-cyclopentyl-2-((3aS,6S,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)benzamide

HPLC-MS R_(t)=3.41 min, 525.3 [M+H]⁺, 543.3 [M+H+18]⁺, 1071.5 [2M+Na]⁺.

Example 67N—((S)-1-cyclopentyl-2-((3aS,6S,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-ethylpiperidin-1-yl)benzamide

HPLC-MS R_(t)=3.34 min, 498.3 [M+H]⁺, 516.3 [M+H+18]⁺.

Example 68N—((S)-1-cyclopentyl-2-((3aS,6S,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-propylpiperidin-1-yl)benzamide

HPLC-MS R_(t)=3.57 min, 512.3 [M+H]⁺, 530.3 [M+H+18]⁺, 1045.5 [2M+Na]⁺.

Example 69N—((S)-1-cyclopentyl-2-((3aS,6S,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-isopropylpiperidin-1-yl)benzamide

HPLC-MS R_(t)=3.51 min, 512.3 [M+H]⁺, 530.3 [M+H+18]⁺.

Example 70N—((S)-1-cyclopentyl-2-((3aS,6S,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(1-(2-methoxyethyl)piperidin-4-yl)benzamide

HPLC-MS R_(t)=3.45 min, 528.3 [M+H]⁺, 546.3 [M+H+18]⁺.

Example 71N—((S)-1-cyclopentyl-2-((3aS,6S,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(1-cyclopropylpiperidin-4-yl)benzamide

HPLC-MS R_(t)=3.47 min, 510.3 [M+H]⁺, 528.3 [M+H+18]⁺, 1041.5 [2M+Na]⁺.

Example 724-(1-cyclobutylpiperidin-4-yl)-N—((S)-1-cyclopentyl-2-((3aS,6S,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)benzamide

HPLC-MS R_(t)=3.62 min, 524.3 [M+H]⁺, 542.3 [M+H+18]⁺, 1069.5 [2M+Na]⁺.

Example 73N—((S)-1-((3aS,6R,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxobutan-2-yl)-4-(4-methylpiperazin-1-yl)benzamide

HPLC-MS R_(t)=2.70 min, 473.2 [M+H]⁺, 491.2 [M+H+18]⁺.

Example 74N-((2S,3S)-1-((3aS,6R,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)-4-(4-methylpiperazin-1-yl)benzamide

HPLC-MS R_(t)=2.72 min, 473.2 [M+H]⁺, 491.2 [M+H+18]⁺.

Example 75N—((S)-1-cyclopentyl-2-((3aS,6R,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-ethylpiperazin-1-yl)benzamide

HPLC-MS R_(t)=2.96 min, 499.3 [M+H]⁺, 517.3 [M+H+18]⁺.

Example 76N—((S)-1-cyclopentyl-2-((3aS,6R,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-(2-methoxyethyl)piperazin-1-yl)benzamide

HPLC-MS R_(t)=3.05 min, 529.3 [M+H]⁺, 547.3 [M+H+18]⁺.

Example 77N—((S)-1-cyclopentyl-2-((3aS,6R,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-methylpiperazin-1-yl)benzamide

HPLC-MS R_(t)=2.76 min, 485.3 [M+H]⁺, 503.3 [M+H+18]⁺.

Example 78N—((S)-1-cyclopentyl-2-((3aS,6S,6aS)-6-methylthio-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-methylpiperazin-1-yl)benzamide

HPLC-MS R_(t)=3.50 min, 501.1 [M+H]⁺, 519.2 [M+H+18]⁺.

Example 79N—((S)-1-cyclopentyl-2-((3aS,6S,6aS)-6-methylsulfinyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-methylpiperazin-1-yl)benzamide

Prepared from (EXAMPLE 78) with oxidation whilst on solid phase usingDess Martin periodinane in DCM overnight;

HPLC-MS R_(t)=2.23 min, 517.2 [M+H]⁺, 535.2 [M+H+18]⁺.

Solution Phase Syntheses.

Alternatively, examples of the invention may be prepared by traditionalsolution phase organic chemistry techniques commencing from buildingblocks such as(3R,3aR,6S,6aS)-6-methoxyhexahydro-2H-furo[3,2-b]pyrrol-3-ol or(3R,3aR,6R,6aS)-6-methoxyhexahydro-2H-furo[3,2-b]pyrrol-3-ol forexample.

Alternative Preparation of4-(4-isopropylpiperazin-1-yl)-N—((S)-1-((3aS,6R,6aS-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)benzamideExample 22 (i) Preparation of tert-Butyl(S)-1-((3R,3aR,6R,6aS)-3-hydroxy-6-methoxydihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-ylcarbamate

Palladium on charcoal (10%, 285 mg) was added to a solution containing a3:1 mixture of benzyl(R)-2-((1S,2R,5S)-3,6-dioxabicyclo[3.1.0]hexan-2-yl)-2-methoxyethylcarbamate (31) and benzyl(R)-2-((1R,2R,5R)-3,6-dioxabicyclo[3.1.0]hexan-2-yl)-2-methoxyethylcarbamate (31b) respectively (2.85 g, 9.73 mmol) in ethanol (130 mL)under an atmosphere of argon. The argon was replaced by hydrogen thenthe suspension was stirred for 80 minutes then filtered through celitein vacuo. The filter cake was washed with ethanol then the solventsremoved in vacuo from the filtrate. The residue was azeotroped withtoluene to obtain the crude(3R,3aR,6R,6aS)-6-methoxyhexahydro-2H-furo[3,2-b]pyrrol-3-ol which wasused without further purification.

A solution of (S)-tert-butyl1-fluoro-4,4-dimethyl-1-oxopentan-2-ylcarbamate (2.64 g, 10.7 mmol) indimethylformamide (25 mL) was added under argon to a solution of(3R,3aR,6aR)-hexahydro-2H-furo[3,2-b]pyrrol-3-ol hydrochloride (assumedto be 9.73 mmol) in dimethylformamide (25 mL). The mixture was stirredfor 1 hour then (S)-tert-butyl1-fluoro-4,4-dimethyl-1-oxopentan-2-ylcarbamate (0.59 g, 2.4 mmol) wasadded. The mixture was stirred for 2 hours then the solvents removed invacuo. The residue was diluted with brine (250 mL) then extracted withdichloromethane (3×100 mL). The combined organic layers were dried(Na₂SO₄), filtered and reduced in vacuo. Flash chromatography oversilica, eluting with ethyl acetate:heptane mixtures 50:50 to 100:0 gavetert-butyl(S)-1-((3R,3aR,6R,6aS)-3-hydroxy-6-methoxydihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-ylcarbamateas a yellow solid (1.73 g, 61% calculated from amount of benzyl(R)-2-((1S,2R,5S)-3,6-dioxabicyclo[3.1.0]hexan-2-yl)-2-methoxyethylcarbamate present in the starting material). TLC (R_(f)=0.10,EtOAc:heptane 2:1), analytical HPLC main peak, R_(t)=13.445 min.,HPLC-MS 331.2 [M+2H−^(t)Bu]⁺, 387.2 [M+H]⁺, 409.2 [M+Na]⁺, 795.4[2M+Na]⁺; [□]_(D) ²⁰+14.03° (c=1.96, CHCl₃); δ_(H) (500 MHz, CDCl₃)mixture of rotamers major:minor 4:3; 0.95 (9H, s, CH₂C(CH₃)₃), 1.40 (9H,s, OC(CH 3)₃), 1.38-1.55 (1.57H, m, CH₂C(CH₃)₃), 1.58 (0.43H, dd, 9.24Hz, CH₂C(CH₃)₃ minor), 3.18 (0.43H, dd, J=11.56 and 9.58 Hz, NCH₂CHOCH₃minor), 3.31 (0.57H, t, J=9.42 Hz, NCH₂CHOCH₃ major), 3.38 (0.43H, brs,OH minor), 3.45 (1.29H, s, OCH₃ minor), 3.47 (1.71H, s, OCH₃ major),3.62 (0.43H, dd, 6.23 Hz, OCH₂CHOH minor), 3.71-3.76 (0.43H, m, CHOCH₃minor), 3.78 (0.57H, dd, 4.23 Hz, OCH₂CHOH major), 3.88-3.93 (0.53H, m,CHOCH₃ major), 4.00-4.06 (1H, m, OCH₂CHOH major and NCH₂CHOCH₃ minor),4.11 (0.53H, dd, 7.36 Hz, NCH₂CHOCH₃ major), 4.24-4.34 (2.43H, m,OCH₂CHOHCH and OCH₂CHOH minor), 4.45-4.51 (0.43H, m, CHCH₂C(CH₃)₃minor), 4.67-4.73 (1.57H, m, CHCHOCH₃ and CHCH₂C(CH₃)₃ major), 5.14(0.43H, d, J=9.35 Hz, NH minor), 5.27 (0.57H, d, J=10.03 Hz, NH major),5.54 (0.57H, d, J=5.30 Hz, OH major); δ_(C) (125 MHz, CDCl₃) 28.27/28.36(OC(CH₃)₃), 29.71/29.85 (CH₂C(CH₃)₃), 30.55/30.65 (CH₂C(CH₃)₃),46.14/46.96 (CH₂C(CH₃)₃), 46.56/48.56 (NCH₂CHOCH₃), 48.72/49.46(CHCH₂C(CH₃)₃), 58.02/58.10 (OCH₃), 69.96/70.33 (OCH₂CHOHCH),74.08/74.98 (OCH₂CHOH), 76.37/79.71 (CHOH), 77.96/79.42 (CHOCH₃),78.44/80.45 (OCHCHOCH₃), 79.82/80.45 (OC(CH₃)₃), 155.31/156.06 (BocC═O), 172.64/173.24 (CH₂NC═O).

(ii) Preparation of(S)-2-Amino-1-((3R,3aR,6R,6aS)-3-hydroxy-6-methoxydihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethylpentan-1-onehydrochloride

A solution of HCl in 1,4-dioxane (4.0M, 25 mL, 100 mmol) was added totert-butyl(S)-1-((3R,3aR,6R,6aS)-3-hydroxy-6-methoxydihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-ylcarbamate(1.73 g, 4.48 mmol). The solution was stirred for 2 hours then thesolvents were removed in vacuo and the residue azeotroped with toluene(1×50 mL then 1×25 mL) to leave(S)-2-amino-1-((3R,3aR,6R,6aS)-3-hydroxy-6-methoxydihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethylpentan-1-onehydrochloride as an off-white solid which was used without furtherpurification. TLC (R_(f)=0.0, EtOAc:heptane 2:1), analytical HPLC mainpeak, R_(t)=4.047 min., HPLC-MS 287.2 [M+H]⁺, 595.3 [2M+Na]⁺; δ_(C) (125MHz, CD₃OH) 29.66 (C(CH₃)₃), 30.45 (C(CH₃)₃), 44.51/49.24 (NCH₂CHOCH₃and CH₂C(CH₃)₃), 50.03 (CHCH₂C(CH₃)₃), 57.85 (OCH₃), 70.64 (CHCHOH),74.83 (CHCHOH), 75.56 (CH₂CHOH), 78.13 and 79.11 (CHCHOCH₃),169.80/169.98 (NC═O).

(iii) Preparation ofN—((S)-1-((3R,3aR,6R,6aS)-3-Hydroxy-6-methoxydihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)-4-(4-isopropylpiperazin-1-yl)benzamide

4-Methylmorpholine (0.98 mL, 8.9 mmol) was added to a suspension of2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate(HBTU, 1.69 g, 4.45 mmol), 1-hydroxybenzotriazole monohydrate (0.68 g,4.45 mmol) and 4-(4-isopropylpiperazin-1-yl)benzoic acid (82% wt., 1.41g, 4.66 mmol) in dimethylformamide (8 mL). The suspension was sonicatedfor 3 minutes then added to(S)-2-amino-1-((3R,3aR,6R,6aS)-3-hydroxy-6-methoxydihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethylpentan-1-onehydrochloride (prepared as above, assume 4.24 mmol). After 2.5 hourssaturated sodium hydrogen carbonate solution (50 mL) was added then theaqueous phase was extracted with dichloromethane (3×20 mL). The combinedorganic layers were washed with brine (50 mL), then dried (Na₂SO₄),filtered and reduced in vacuo. Flash chromatography over silica, elutingwith methanol:dichloromethane mixtures 0:100 to 10:90 gaveN—((S)-1-((3R,3aR,6R,6aS)-3-hydroxy-6-methoxydihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)-4-(4-isopropylpiperazin-1yl)benzamideas a pale yellow solid (1.77 g, 81%). TLC (R_(f)=0.10-0.15 double spot,MeOH:CH₂Cl₂ 5:95), analytical HPLC main peak, R_(t)=10.16 min., HPLC-MS517.4 [M+H]⁺, 1033.7 [2M+Na]⁺; [□]_(D) ¹⁹+28.85° (c=3.64, CHCl₃); δ_(H)(500 MHz, CDCl₃) mixture of rotamers major:minor 5:3; 0.98 (9H, s,C(CH₃)₃), 1.08 (3.78H, d, J=6.53 Hz, NCH(CH₃)₂ major), 1.09 (2.22H, d,J=6.52 Hz, NCH(CH₃)₂ minor), 1.58-1.67 (1.37H, m, CH₂C(CH₃)₃), 1.76(0.63H, dd, 9.43 Hz, CH₂C(CH₃)₃ major), 2.64-2.69 (4H, m,CH₂CH₂NCH(CH₃)₂), 2.69-2.76 (1H, m, NCH(CH₃)₂), 3.18 (0.63H, dd, 9.63Hz, NCH₂CHOCH₃ major), 3.27-3.33 (4H, m, CH₂CH₂NCH₃), 3.37 (0.37H, brt,J=9.45 Hz, NCH₂CHOCH₃ minor), 3.46 (1.89H, s, OCH₃ major), 3.48 (1.11H,s, OCH₃ minor), 3.63 (0.63H, dd, 6.40 Hz, OCH₂CHOH major), 3.74-3.78(0.63H, m, CHOCH₃ major), 3.79 (0.37H, dd, 4.09 Hz, OCH₂CHOH minor),3.92-3.96 (0.37H, m, CHOCH₃ minor), 4.03-4.09 (1H, m, NCH₂CHOCH₃),4.28-4.38 (3H, m, OCH₂CHOHCH and 1×OCH₂CHOH), 4.67 (0.37H, brt, J=4.59Hz, OCHCHOCH₃ minor), 4.72 (0.63H, brt, J=5.04 Hz, OCHCHOCH₃ major),4.97-5.03 (0.37H, m, CHCH₂C(CH₃)₃ minor), 5.24-5.29 (0.63H, m,CHCH₂C(CH₃)₃ major), 5.96 (0.63H, brs, OH major), 6.62 (0.37H, d, J=8.39Hz, NH minor), 6.71 (0.63H, d, J=9.83 Hz, NH major), 6.82-6.87 (2H, m,aromatic CH), 7.66-7.70 (2H, m, aromatic CH); δ_(C) (125 MHz, CDCl₃)18.50 (CH(CH₃)₂, 29.79/29.91 (C(CH₃)₃), 30.71/30.75 (C(CH₃)₃),46.18/47.10 (CH₂C(CH₃)₃), 46.56 (NCH₂CHOCH₃), 47.82/48.30(CHCH₂C(CH₃)₃), 47.87/49.01 (NCH₂CH₂NCH(CH₃)₂), 48.40/48.44(NCH₂CH₂NCH(CH₃)₂), 54.56/54.60 (NCH(CH₃)₂), 58.06/58.03 (OCH₃),69.93/70.56 (OCH₂CHOHCH), 74.01/75.01 (OCH₂CHOH), 76.35/79.85 (CHOH),77.94/79.41 (CHOCH₃), 78.54/80.45 (OCHCHOCH₃), 113.92/114.06/128.52 and128.73 (aromatic CH), 122.18/123.16 (aromatic quaternary), 153.53/153.80(aromatic quaternary), 166.57/167.19 (NHC═O), 172.37/173.13 (CH₂NC═O).

(iv) Oxidation to Example 22

Dess-Martin periodinane (2.82 g, 6.66 mmol) was added to a stirredsolution ofN—((S)-1-((3R,3aR,6R,6aS)-3-hydroxy-6-methoxydihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)-4-(4-isopropylpiperazin-1yl)benzamide(1.72 g, 3.33 mmol) in dichloromethane (65 mL) under an atmosphere ofargon. The mixture was stirred for 18 hours then diluted withdichloromethane (300 mL). The organic phase was washed with aqueoussodium hydroxide solution (1M, 100 mL) then the aqueous extracted withdichloromethane (150 mL). The organic layer was washed with aqueoussodium hydroxide solution (1M, 100 mL) then brine (150 mL), then dried(Na₂SO₄), filtered and reduced in vacuo to give4-(4-isopropylpiperazin-1-yl)-N—((S)-1-((3aS,6R,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)benzamidea pale yellow solid (1.408 g, 82%). TLC (R_(f)=0.45, MeOH:CH₂Cl₂ 1:19),analytical HPLC main peak, R_(t)=10.39 min., HPLC-MS 515.3 [M+H]⁺, 533.3[M+H₂O+H]⁺, 1051.6 [2M+Na]⁺; [□]_(D) ²²−31.08° (c=3.7, CHCl₃); δ_(H)(500 MHz, CDCl₃) 0.99 (9H, s, C(CH₃)₃), 1.08 (6H, d, J=6.52 Hz,NCH(CH₃)₂), 1.68-1.74 (2H, m, CH₂C(CH₃)₃), 2.65 (4H, brt, J=5.04 Hz,CH₂NCH(CH₃)₂), 2.67-2.73 (1H, m, NCH(CH₃)₂), 3.29 (4H, brt, J=5.05 Hz,CH₂CH₂NCH(CH₃)₂), 3.49 (3H, s, OCH₃), 3.61 (1H, dd, 5.35 Hz,NCH₂CHOCH₃), 4.00-4.04 (1H, m, CHOCH₃), 4.09 (1H, d, J=16.89 Hz,OCH₂C═O), 4.20 (1H, d, J=16.93 Hz, OCH₂C═O), 4.27 (1H, dd, 5.88 Hz,NCH₂CHOCH₃), 4.74 (1H, d, J=6.86 Hz, OCH₂(C═O)CH), 4.91 (1H, dd, 4.28Hz, OCHCHOCH₃), 4.94-5.00 (1H, m, CHCH₂C(CH₃)₃), 6.61 (1H, d, J=8.69 Hz,NH), 6.84 (2H, brd, J=8.95 Hz, aromatic CH), 7.65 (2H, brd, J=8.91 Hz,aromatic CH); δ_(C) (125 MHz, CDCl₃) 18.53 (NCH(CH₃)₂), 29.75/29.80(C(CH₃)₃), 30.75/30.77 (C(CH₃)₃), 46.53 (CH₂C(CH₃)₃), 47.02(NCH₂CH₂NCH(CH₃)₂), 48.24 (CHCH₂C(CH₃)₃), 48.43 (NCH₂CH₂NCH(CH₃)₂),49.76 (NCH₂CHOCH₃), 54.49 (NCH(CH₃)₂), 58.23 (OCH₃), 60.49(OCH₂C(═O)CH), 71.45 (OCH₂C═O), 78.84 (CHOCH₃), 80.25 (OCHCHOCH₃),114.01/114.10/128.49 and 129.83 (aromatic CH), 123.08 (aromaticquaternary), 153.55 (aromatic quaternary), 166.69 (NHC═O), 173.53(CH₂NC═O), 207.93 (ketone C═O).

Formation of Example. Hydrochloride Salt.

EXAMPLE ketone (free base) (1 mmol) was dissolved in acetonitrile (16.7mL) and standardised 0.1N HCl (1.5 eq, 15.0 mL) was added. The mixturewas frozen and lyophilised to leave the EXAMPLE hydrochloride salt as asolid.

Example A Assays for Cysteine Protease Activity

The compounds of this invention may be tested in one of a number ofliterature based biochemical assays that are designed to elucidate thecharacteristics of compound inhibition. The data from these types ofassays enables compound potency and the rates of reaction to be measuredand quantified. This information, either alone or in combination withother information, would allow the amount of compound required toproduce a given pharmacological effect to be determined.

In Vitro Cathepsin Ki Inhibition Measurements

Stock solutions of substrate or inhibitor were made up to 10 mM in 100%dimethylsulfoxide (DMSO) (Rathburns, Glasgow, U.K.) and diluted asappropriately required. In all cases the DMSO concentration in theassays was maintained at less than 1% (vol./vol.). The equilibriuminhibition constants (K_(i) ^(SS)) for each compound were measured understeady-state conditions monitoring enzyme activity as a function ofinhibitor concentration. The values were calculated on the assumption ofpure competitive behaviour (Cornish-Bowden, A. Fundamentals of enzymekinetics Portland Press; 1995, 93-128). Human recombinant cathepsin K(0.25 nM final; B. Turk, Josef, Stefan Institute, Ljubljana, Slovenia),was routinely assayed in 100 mM sodium acetate; pH 5.5 containing 1 mMEDTA, 10 mM L-cysteine and 1.8 μM Z-Leu-Arg-AMC ([S]═K_(M)).

Measurement of the Apparent Macroscopic Binding (Michaelis) Constants(K_(M) ^(app)) for Substrates

The apparent macroscopic binding constant (K_(M) ^(aPP)) for eachsubstrate was calculated, from the dependence of enzyme activity as afunction of substrate concentration. The observed rates were plotted onthe ordinate against the related substrate concentration on the abscissaand the data fitted by direct regression analysis (Prism v 3.02;GraphPad, San Diego, USA) using Equation 1 (Cornish-Bowden, A.Fundamentals of enzyme kinetics Portland Press; 1995, 93-128).

$\begin{matrix}{v_{i} = \frac{V_{\max}^{app} \cdot \left\lbrack S_{o} \right\rbrack}{\left\lbrack S_{o} \right\rbrack + K_{M}^{app}}} & (1)\end{matrix}$

In Equation 1 ‘v_(i)’ is the observed initial rate, ‘V_(max) ^(app)’ isthe observed maximum activity at saturating substrate concentration,‘K_(M) ^(app)’ is the apparent macroscopic binding (Michaelis) constantfor the substrate, ‘[S_(o)]’ is the initial substrate concentration.

Measurement of the Inhibition Constants

The apparent inhibition constant (K_(i)) for each compound wasdetermined on the basis that inhibition was reversible and occurred by apure-competitive mechanism. The K_(i) values were calculated, from thedependence of enzyme activity as a function of inhibitor concentration,by direct regression analysis (Prism v 3.02) using Equation 2(Cornish-Bowden, A., 1995).

$\begin{matrix}{v_{i} = \frac{V_{\max}^{app} \cdot \lbrack S\rbrack}{\lbrack S\rbrack + \left\{ {K_{M}^{app} \cdot \left( {\lbrack I\rbrack/K_{i}} \right)} \right\}}} & (2)\end{matrix}$

In Equation 2 ‘v_(i)’ is the observed residual activity, ‘V_(max)^(app)’ is the observed maximum activity (i.e. in the absence ofinhibitor), ‘K_(M) ^(app)’ is the apparent macroscopic binding(Michaelis) constant for the substrate, ‘[S]’ is the initial substrateconcentration, ‘K_(i)’ is the apparent dissociation constant and ‘[I]’is the inhibitor concentration.

In situations where the apparent dissociation constant (K_(i) ^(app))approached the enzyme concentrations, the K_(i) ^(app) values werecalculated using a quadratic solution in the form described by Equation3 (Morrison, J. F. Trends Biochem. Sci., 7, 102-105, 1982; Morrison, J.F. Biochim. Biophys. Acta, 185, 269-286, 1969; Stone, S. R. andHofsteenge, J. Biochemistry, 25, 4622-4628, 1986).

$\begin{matrix}{v_{i} = \frac{F\left\{ {E_{o} - I_{o} - K_{i}^{app} + \sqrt{\begin{matrix}{\left( {E_{o} - I_{o} - K_{i}^{app}} \right)^{2} +} \\{4 \cdot K_{i}^{app} \cdot E_{o}}\end{matrix}}} \right\}}{2}} & (3) \\{K_{i}^{app} = {K_{i}\left( {1 + {\left\lbrack S_{o} \right\rbrack/K_{M}^{app}}} \right)}} & (4)\end{matrix}$

In Equation 3 ‘v_(i)’ is the observed residual activity, ‘F’ is thedifference between the maximum activity (i.e. in the absence ofinhibitor) and minimum enzyme activity, ‘E_(o)’ is the total enzymeconcentration, ‘K_(i) ^(app)’ is the apparent dissociation constant and‘I_(o)’ is the inhibitor concentration. Curves were fitted by non-linearregression analysis (Prism) using a fixed value for the enzymeconcentration. Equation 4 was used to account for the substratekinetics, where ‘K_(i)’ is the inhibition constant, ‘[S_(o)]’ is theinitial substrate concentration and ‘K_(M) ^(app)’ is the apparentmacroscopic binding (Michaelis) constant for the substrate (Morrison,1982).

The Second-Order Rate of Reaction of Inhibitor with Enzyme

Where applicable, the concentration dependence of the observed rate ofreaction (k_(obs)) of each compound with enzyme was analysed bydetermining the rate of enzyme inactivation under pseudo-first orderconditions in the presence of substrate (Morrison, J. F., TIBS, 102-105,1982; Tian, W. X. and Tsou, C. L., Biochemistry, 21, 1028-1032, 1982;Morrison, J. F. and Walsh, C. T., from Meister (Ed.), Advances inEnzymol., 61, 201-301, 1988; Tsou, C. L., from Meister (Ed.), Advancesin Enzymol., 61, 381436, 1988). Assays were carried out by addition ofvarious concentrations of inhibitor to assay buffer containingsubstrate. Assays were initiated by the addition of enzyme to thereaction mixture and the change in fluorescence monitored over time.During the course of the assay less than 10% of the substrate wasconsumed.

$\begin{matrix}{F = {{v_{s}t} + \frac{\left( {v_{o} - v_{s}} \right)\left\lbrack {1 - {\mathbb{e}}^{({k_{obs} \cdot t})}} \right\rbrack}{k_{obs}} + D}} & (5)\end{matrix}$

The activity fluorescence progress curves were fitted by non-linearregression analysis (Prism) using Eq. 5 (Morrison, 1969; Morrison,1982); where ‘F’ is the fluorescence response, ‘t’ is time, ‘v_(o)’ isthe initial velocity, ‘v_(s)’ is the equilibrium steady-state velocity,‘k_(obs)’ is the observed pseudo first-order rate constant and ‘D’ isthe intercept at time zero (i.e. the ordinate displacement of thecurve). The second order rate constant was obtained from the slope ofthe line of a plot of k_(obs) versus the inhibitor concentration (i.e.k_(obs)/[I]). To correct for substrate kinetics, Eq. 6 was used, where‘[S_(o)]’ is the initial substrate concentration and ‘K_(M) ^(app)’ isthe apparent macroscopic binding (Michaelis) constant for the substrate.

$\begin{matrix}{k_{inact} = \frac{k_{obs}\left( {1 + {\left\lbrack S_{o} \right\rbrack/K_{M}^{app}}} \right)}{\lbrack I\rbrack}} & (6)\end{matrix}$

Compounds of the invention were tested by the above described assays andobserved to exhibit cathepsin K inhibitory activity with an in vitro Kiinhibitory constant of less than or equal to 100 nM.

Liver Microsomal Incubations:

Human and rat liver microsomes were purchased from BD Gentest (Woburn,Mass., USA) and β-nicotinamide adenine dinucleotide 2′-phosphate reducedtetrasodium salt (NADPH) was purchased from Sigma-Aldrich (Poole,Dorset, UK). All liver microsome incubations were carried out in 50 mMpotassium phosphate buffer at pH 7.4, with a final microsomal proteinconcentration of 0.5 mg/mL. Compounds were taken from 5 mM DMSO stocksolutions and diluted in incubation buffer to give a final concentrationof 25 μM, with a final DMSO concentration of 0.5% v/v. In brief,compounds were added to the incubation buffer along with the livermicrosomes and incubated at 37° C. for 10 minutes. The reaction was theninitiated by the addition of NADPH, previously dissolved in incubationbuffer, to give a final concentration of 1 mM and re-incubated at 37° C.Aliquots were removed at 2 and 60 minutes and quenched with an equalvolume of cold acetonitrile. After mixing vigorously, the precipitatedprotein matter was removed by filtration (Multiscreen Solvinert filterplates, Millipore, Bedford, Mass., USA) and the filtrate analysed byreverse phase HPLC with mass spectrometric detection, using single ionmonitoring of the [M+H]⁺ species. Metabolic turnover was determined bycomparison of peak areas from the ion chromatograms of the parentcompound at 2 and 60 minutes and expressed as percent remaining at 1hour.

Plasma Incubations:

Human and rat plasma were purchased from Innovative Research Inc.(Southfield. MI, USA). Compounds were taken from 5 mM DMSO stocksolutions and added to plasma, which had previously been incubated at37° C., to give a final concentration of 25 μM and re-incubated.Aliquots were removed at 2 and 60 minutes and quenched with an equalvolume of cold acetonitrile. After mixing vigorously, the precipitatedprotein matter was removed by filtration (Multiscreen Solvinert filterplates, Millipore, Bedford, Mass., USA) and the filtrate analysed byreverse phase HPLC with mass spectrometric detection, using single ionmonitoring of the [M+H]⁺ species. Metabolic turnover was determined bycomparison of peak areas from the ion chromatograms of the parentcompound at 2 and 60 minutes and expressed as percent remaining at 1hour.

LogD Determinations:

LogD_((PBS)) determinations were performed in 96 well microtitre platesusing a miniaturised “shake-flask” method. In brief, compounds weretaken from 10 mM DMSO stock solutions and added to wells containingequal volumes of phosphate buffered saline (10 mM; pH 7.4) (PBS) and1-octanol (Sigma-Aldrich, Poole, Dorset, UK) to give a finalconcentration of 50 μM. The plates were then capped and mixed vigorouslyfor 1 hour on a microtitre plate shaker, after which they were left tostand, allowing the PBS and octanol phases to separate. The PBS layerwas analysed by reverse phase HPLC with mass spectrometric detection,using single ion monitoring of the [M+H]⁺ species. LogD_((PBS)) wasdetermined by comparison of the peak area from the ion chromatogram ofthe compound in the PBS phase with that of a 50 μM standard of the samecompound dissolved in acetonitrile/water (50:50) and calculated usingthe following formula:

${{Log}\; D} = {{Log}\left\lbrack \frac{{AUCstd} - {AUCpbs}}{AUCpbs} \right\rbrack}$

Where AUCstd and AUCpbs are the peak areas from the standard and testion chromatograms respectively. LogD_((PBs)) determinations were alsomade using PBS at pH6.9 and 5.5 by adjusting the pH of the buffer priorto the start of the assay, with 0.1 M HCL.

Human Osteoclast Resorption Assay

Bone resorption was studied using a model where human osteoclastprecursor cells were cultured on bovine bone slices for 9 days andallowed to differentiate into bone-resorbing osteoclasts. The formedmature osteoclasts were then allowed to resorb bone. The assay wasperformed by Pharmatest Services Ltd, Itäinen Pitkakatu 4C, Turku,Finland. After the culture period, bone collagen degradation productswere quantified from the culture medium as an index of bone resorption.Inhibitor compounds were added into the cell cultures after thedifferentiation period and their effects on the resorbing activity ofmature osteoclasts were determined. The studies included a baselinegroup without added compounds and a positive control group where apotent cathepsin K inhibitor E-64 was added.

Human peripheral blood monocytes were suspended to culture medium andallowed to attach to bovine bone slices. The bone slices weretransferred into 96-well tissue culture plates containing culture mediumwith appropriate amounts of important growth factors favouringosteoclast differentiation, including M-CSF, RANK-ligand and TGF-□. Thecells were incubated in a CO₂ incubator in humidified atmosphere of 95%air and 5% carbon dioxide at 37° C. At day 7 when osteoclastdifferentiation was complete, the culture medium was replaced withculture medium containing conditions favouring osteoclast activity. Thecell culture was continued for an additional 2 days, during which theformed mature osteoclasts were allowed to resorb bone in the presence ofvehicle, control inhibitor (E64) or test compounds. At the end of theculture, bone collagen degradation products released into the culturemedium were determined using a commercially available ELISA method(CrossLaps® for culture, Nordic Bioscience, Herlev, Denmark) as an indexof bone resorption (see Bagger, Y. Z. et al, J. Bone. Miner. Res. 14(suppl. 1), S370).

In this assay, selected EXAMPLES of the invention exhibited more than75% inhibition of bone resorption at a concentration of 1000 nM.

Rat Osteoclast Resorption Assay

Bone resorption was studied using a model where mature osteoclastsderived from rat bone were cultured on bovine bone slices for 3 days andallowed to resorb bone in the presence of inhibitor, positive control(E-64) or vehicle. More specifically, tibia, femori and humeri wereremoved from 1 day old rat pups. The endosteal surfaces of the boneswere scraped with a scalpel to release osteoclasts into the culturemedium and the osteoclasts were allowed to attach to bovine bone slices.After the culture period, bone collagen degradation products werequantified from the culture medium as an index of bone resorption. Theassay was performed by Pharmatest Services Ltd, Itäinen Pitkakatu 4C,Turku, Finland.

In this assay, selected EXAMPLES of the invention exhibited more than75% inhibition of bone resorption at a concentration of 1000 nM.

TABLE 1 Comparison of biological properties for a selection of preferredcompounds and prior art compounds 23/10 and 42/45a Cell-based Human Invitro Ki % Inh. @ Plasma (nM) vs 1 □ M Stability % LogD EXAMPLE Cath KHuman rem. @ 1 h pH 7.4

87.4 Lit. 60 75 1.36

8.7 55 95 Lit. 0.04* 0.56** *UV method **Ion- count method

5.6 81 96 1.18

6.3 69 93 1.00

15.1 54 87 0.42

5.6 66 89 0.84

5.8 79 96 1.05

5.1 87 100 1.46

9.9 63 93 0.89

9.2 71 92 1.09

3.9 88 93 1.64

8.6 84 98 1.74

16.3 76 92 1.34

3.7 82 97 1.69

8.4 78 91 1.2

11.2 25 88 0.55

3.5 49 96 0.01

6.9 45 92 0.56

8.1 42 95 0.23

6.3 82 99 1.23

14.4 44 88 0.76

8.2 70 99 1.12

1.8 IC₅₀ = 52 nM 93.6 1.36

3.6 — 90.9 1.59

4.9 IC₅₀ = 637 nM 91.8 0.75

3.4 IC₅₀ = 231 nM 90.7 0.95

TABLE 2 Prior art WO-A-02057270 in vitro Ki against recombinant humancathepsin K. Example No (WO- Ki (nM) vs Human A-02057270) Cathepsin K1 >20000 2 >50000 3 >4000 4 >100000 5 >100000 6 >20000 7 >15000 8 390 990 10 87 11 1300 12 170 13 560 14 300 15 60 16 110 17 235 18 130 19 53020 390 21 210 22 450 23 >3000 24 >2000 25 620 26 >8000 27 >2000028 >2500 29 >17000 30 >100000 31 >1500 32 >16000 33 >36000 34 >6700035 >32000 36 570 37 >3500 38 >4000 39 >7500 40 >3500 41 >45000 42 >150043 >25000 44 >40000 45 >8500 46 >20000 47 830 48 >6500 49 >600050 >10000 51 >1500 52 >25000 53 200 54 >2000 55 >2000 56 >4000 57 39058 >23000 59 >2000 60 >20000 61 >16000 62 >10000 63 >250 64 >8000 65 10066 >2500 67 >2000 68 >2500 69 >15000 70 >2500 71 >20000 72 >2000073 >35000 74 >40000 75 >50000 76 >10000 77 >100000 78 >2000 79 >20080 >150 81 >50000 82 >50000 Selected compounds of the present inventionare significantly more potent than those specifically detailed in priorart WO-A-02057270 when assayed in vitro against recombinant humancathepsin K (compare tables 1 and 2).

Various modifications and variations of the described aspects of theinvention will be apparent to those skilled in the art without departingfrom the scope and spirit of the invention. Although the invention hasbeen described in connection with specific preferred embodiments, itshould be understood that the invention as claimed should not be undulylimited to such specific embodiments. Indeed, various modifications ofthe described modes of carrying out the invention which are obvious tothose skilled in the relevant fields are intended to be within the scopeof the following claims.

1. A compound of formula (I), or a pharmaceutically acceptable salt,hydrate, ketal derivative or hemiketal derivative thereof,

wherein: X is CH or N; one of R¹ and R² is H, and the other is selectedfrom OH, OMe, OEt, O^(n)Pr, O^(i)Pr, O-cyclopropyl, O-cyclobutyl, SH,SMe, SEt, S^(n)Pr, S^(i)Pr, S-cyclopropyl, S-cyclobutyl, NH₂, NHMe,NHEt, NH^(n)Pr, NH^(i)Pr, NH-cyclopropyl, NH-cyclobutyl, NMe₂, N₃, SOMe,SOEt, SO^(n)Pr, SO^(i)Pr, SO-cyclopropyl, SO-cyclobutyl, SO₂Me, SO₂Et,SO₂ ^(n)Pr, SO₂ ^(i)Pr, SO₂-cyclopropyl, SO₂-cyclobutyl, and

R³ is selected from tert-butylmethyl, iso-propylmethyl, sec-butyl,tert-butyl, cyclopentyl and cyclohexyl; R⁴ is C₁₋₈ alkyl that isunsubstituted or substituted; or C₃₋₈ cycloalkyl that is unsubstitutedor substituted.
 2. A compound according to claim 1 wherein said compoundis of formula Ia

wherein X, R¹, R², R³ and R⁴ are as defined in claim
 1. 3. A compoundaccording to claim 1 wherein X is CH.
 4. A compound according to claim 1wherein X is N.
 5. A compound according to claim 1 wherein R⁴ is anunsubstituted C₃₋₆ cycloalkyl group.
 6. A compound according to claim 1wherein R⁴ is a C₁₋₆ alkyl group that is unsubstituted or substituted byone or more C₁₋₆ alkoxy groups.
 7. A compound according to claim 1wherein R⁴ is selected from methyl, ethyl, n-propyl, iso-propyl,cyclopropyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, cyclobutyl and2-methoxyethyl.
 8. A compound according to claim 7 wherein R⁴ isselected from methyl, ethyl, n-propyl, isopropyl, cyclopropyl,cyclobutyl and 2-methoxyethyl.
 9. A compound according to claim 1wherein R³ is selected from tert-butylmethyl, sec-butyl, tert-butyl,cyclopentyl and cyclohexyl.
 10. A compound according to claim 1 whereinR³ is cyclopentyl or cyclohexyl.
 11. A compound according to claim 1,wherein one of R¹ and R² is H, and the other is selected from OH, OMe,OEt, O^(n)Pr, O^(i)Pr, O-cyclopropyl, O-cyclobutyl, SH, SMe, SEt,S^(n)Pr, S^(i)Pr, S-cyclopropyl, S cyclobutyl, NH₂, NHMe, NHEt,NH^(n)Pr, NH^(i)Pr, NH-cyclopropyl, NH-cyclobutyl, and NMe₂.
 12. Acompound according to claim 1 wherein one of R¹ and R² is H, and theother is selected from OH, OMe, OEt, O^(n)Pr, O^(i)Pr, O-cyclopropyl,O-cyclobutyl, SH, SMe, SEt, S^(n)Pr, S^(i)Pr, S-cyclopropyl,S-cyclobutyl, NH₂, NHMe, NHEt, NH^(n)Pr, NH^(i)Pr, NMe₂ and N₃.
 13. Acompound according to claim 12 wherein: R¹ is OH, OMe, OEt, SMe, NH₂,NHMe, NMe₂ or N₃ and R² is H; or R² is OH, OMe, OEt, SMe, NH₂, NHMe,NMe₂ or N₃ and R¹ is H.
 14. A compound according to claim 13 wherein: R¹is OH, OMe, OEt, NH₂, NHMe, SMe or N₃, and R² is H; or R² is OH, OMe,NH₂ or N₃, and R¹ is H.
 15. A compound according to claim 1 which isselected from the following:N—((S)-1-((3aS,6S,6aS)-6-hydroxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)-4-(4-propylpiperazin-1-yl)benzamideN—((S)-1-((3aS,6S,6aS)-6-hydroxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)-4-(4-isopropylpiperazin-1-yl)benzamide4-(4-cyclopropylpiperazin-1-yl)-N—((S)-1-((3aS,6S,6aS)-6-hydroxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)benzamide4-(4-cyclobutylpiperazin-1-yl)-N—((S)-1-((3aS,6S,6aS)-6-hydroxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)benzamide4-(1-cyclopropylpiperidin-4-yl)-N—((S)-1-((3aS,6S,6aS)-6-hydroxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)benzamide4-(1-cyclobutylpiperidin-4-yl)-N—((S)-1-((3aS,6S,6aS)-6-hydroxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)benzamideN—((S)-1-((3aS,6S,6aS)-6-hydroxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)-4-(4-propylpiperazin-1-yl)benzamideN—((S)-1-((3aS,6S,6aS)-6-hydroxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)-4-(4-isopropylpiperazin-1-yl)benzamide4-(4-cyclopropylpiperazin-1-yl)-N—((S)-1-((3aS,6S,6aS)-6-hydroxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)benzamide4-(4-cyclobutylpiperazin-1-yl)-N—((S)-1-((3aS,6S,6aS)-6-hydroxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)benzamide4-(1-cyclopropylpiperidin-4-yl)-N—((S)-1-((3aS,6S,6aS)-6-hydroxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)benzamide4-(1-cyclobutylpiperidin-4-yl)-N—((S)-1-((3aS,6S,6aS)-6-hydroxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)benzamide4-(4-ethylpiperazin-1-yl)-N-((2S,3S)-1-((3aS,6S,6aS)-6-hydroxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)benzamideN-((2S,3S)-1-((3aS,6S,6aS)-6-hydroxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)-4-(4-propylpiperazin-1-yl)benzamideN-((2S,3S)-1-((3aS,6S,6aS)-6-hydroxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)-4-(4-isopropylpiperazin-1-yl)benzamide4-(4-cyclopropylpiperazin-1-yl)-N-((2S,3S)-1-((3aS,6S,6aS)-6-hydroxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)benzamide4-(4-cyclobutylpiperazin-1-yl)-N-((2S,3S)-1-((3aS,6S,6aS)-6-hydroxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)benzamide4-(1-cyclopropylpiperidin-4-yl)-N-((2S,3S)-1-((3aS,6S,6aS)-6-hydroxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)benzamide4-(1-cyclobutylpiperidin-4-yl)-N-((2S,3S)-1-((3aS,6S,6aS)-6-hydroxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)benzamide4-(4-ethylpiperazin-1-yl)-N—((S)-1-((3aS,6S,6aS)-6-hydroxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxobutan-2-yl)benzamideN—((S)-1-((3aS,6S,6aS)-6-hydroxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxobutan-2-yl)-4-(4-propylpiperazin-1-yl)benzamideN—((S)-1-((3aS,6S,6aS)-6-hydroxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxobutan-2-yl)-4-(4-isopropylpiperazin-1-yl)benzamide4-(4-cyclopropylpiperazin-1-yl)-N—((S)-1-((3aS,6S,6aS)-6-hydroxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxobutan-2-yl)benzamide4-(4-cyclobutylpiperazin-1-yl)-N—((S)-1-((3aS,6S,6aS)-6-hydroxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxobutan-2-yl)benzamide4-(1-cyclopropylpiperidin-4-yl)-N—((S)-1-((3aS,6S,6aS)-6-hydroxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxobutan-2-yl)benzamide4-(1-cyclobutylpiperidin-4-yl)-N—((S)-1-((3aS,6S,6aS)-6-hydroxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxobutan-2-yl)benzamideN—((S)-1-cyclopentyl-2-((3aS,6S,6aS)-6-hydroxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-methylpiperazin-1-yl)benzamideN—((S)-1-cyclopentyl-2-((3aS,6S,6aS)-6-hydroxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-ethylpiperazin-1-yl)benzamideN—((S)-1-cyclopentyl-2-((3aS,6S,6aS)-6-hydroxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-propylpiperazin-1-yl)benzamideN—((S)-1-cyclopentyl-2-((3aS,6S,6aS)-6-hydroxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-isopropylpiperazin-1-yl)benzamideN—((S)-1-cyclopentyl-2-((3aS,6S,6aS)-6-hydroxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-(2-methoxyethyl)piperazin-1-yl)benzamideN—((S)-1-cyclopentyl-2-((3aS,6S,6aS)-6-hydroxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-cyclopropylpiperazin-1-yl)benzamide4-(4-cyclobutylpiperazin-1-yl)-N—((S)-1-cyclopentyl-2-((3aS,6S,6aS)-6-hydroxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)benzamideN—((S)-1-cyclopentyl-2-((3aS,6S,6aS)-6-hydroxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(1-propylpiperidin-4-yl)benzamideN—((S)-1-cyclopentyl-2-((3aS,6S,6aS)-6-hydroxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(1-isopropylpiperidin-4-yl)benzamideN—((S)-1-cyclopentyl-2-((3aS,6S,6aS)-6-hydroxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(1-cyclopropylpiperidin-4-yl)benzamide4-(1-cyclobutylpiperidin-4-yl)-N—((S)-1-cyclopentyl-2-((3aS,6S,6aS)-6-hydroxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)benzamideN—((S)-1-cyclohexyl-2-((3aS,6S,6aS)-6-hydroxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-methylpiperazin-1-yl)benzamideN—((S)-1-cyclohexyl-2-((3aS,6S,6aS)-6-hydroxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-ethylpiperazin-1-yl)benzamideN—((S)-1-cyclohexyl-2-((3aS,6S,6aS)-6-hydroxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-propylpiperazin-1-yl)benzamideN—((S)-1-cyclohexyl-2-((3aS,6S,6aS)-6-hydroxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-isopropylpiperazin-1-yl)benzamideN—((S)-1-cyclohexyl-2-((3aS,6S,6aS)-6-hydroxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-(2-methoxyethyl)piperazin-1-yl)benzamideN—((S)-1-cyclohexyl-2-((3aS,6S,6aS)-6-hydroxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-cyclopropylpiperazin-1-yl)benzamide4-(4-cyclobutylpiperazin-1-yl)-N—((S)-1-cyclohexyl-2-((3aS,6S,6aS)-6-hydroxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)benzamideN—((S)-1-cyclohexyl-2-((3aS,6S,6aS)-6-hydroxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(1-propylpiperidin-4-yl)benzamideN—((S)-1-cyclohexyl-2-((3aS,6S,6aS)-6-hydroxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(1-isopropylpiperidin-4-yl)benzamideN—((S)-1-cyclohexyl-2-((3aS,6S,6aS)-6-hydroxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(1-cyclopropylpiperidin-4-yl)benzamide4-(1-cyclobutylpiperidin-4-yl)-N—((S)-1-cyclohexyl-2-((3aS,6S,6aS)-6-hydroxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)benzamideN—((S)-1-((3aS,6S,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)-4-(4-methylpiperazin-1-yl)benzamide4-(4-ethylpiperazin-1-yl)-N—((S)-1-((3aS,6S,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)benzamideN—((S)-1-((3aS,6S,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)-4-(4-propylpiperazin-1-yl)benzamide4-(4-isopropylpiperazin-1-yl)-N—((S)-1-((3aS,6S,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)benzamideN—((S)-1-((3aS,6S,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)-4-(4-(2-methoxyethyl)piperazin-1-yl)benzamide4-(4-cyclopropylpiperazin-1-yl)-N—((S)-1-((3aS,6S,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)benzamide4-(4-cyclobutylpiperazin-1-yl)-N—((S)-1-((3aS,6S,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)benzamideN—((S)-1-((3aS,6S,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)-4-(1-propylpiperidin-4-yl)benzamide4-(1-isopropylpiperidin-4-yl)-N—((S)-1-((3aS,6S,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)benzamideN—((S)-1-((3aS,6S,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)-4-(1-(2-methoxyethyl)piperidin-4-yl)benzamide4-(1-cyclopropylpiperidin-4-yl)-N—((S)-1-((3aS,6S,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)benzamide4-(1-cyclobutylpiperidin-4-yl)-N—((S)-1-((3aS,6S,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)benzamideN—((S)-1-((3aS,6S,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)-4-(4-methylpiperazin-1-yl)benzamide4-(4-ethylpiperazin-1-yl)-N—((S)-1-((3aS,6S,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)benzamideN—((S)-1-((3aS,6S,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)-4-(4-propylpiperazin-1-yl)benzamide4-(4-isopropylpiperazin-1-yl)-N—((S)-1-((3aS,6S,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)benzamideN—((S)-1-((3aS,6S,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)-4-(4-(2-methoxyethyl)piperazin-1-yl)benzamide4-(4-cyclopropylpiperazin-1-yl)-N—((S)-1-((3aS,6S,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)benzamide4-(4-cyclobutylpiperazin-1-yl)-N—((S)-1-((3aS,6S,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)benzamideN—((S)-1((3aS,6S,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-0)-4-(1-propylpiperidin-4-yl)benzamide4-(1-cyclopropylpiperidin-4-yl)-N—((S)-1-((3aS,6S,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)benzamide4-(1-cyclobutylpiperidin-4-yl)-N—((S)-1-((3aS,6S,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)benzamideN-((2S,3S)-1-((3aS,6S,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)-4-(4-methylpiperazin-1-yl)benzamide4-(4-ethylpiperazin-1-yl)-N-((2S,3S)-1-((3aS,6S,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)benzamideN-((2S,3S)-1-((3aS,6S,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)-4-(4-propylpiperazin-1-yl)benzamide4-(4-isopropylpiperazin-1-yl)-N-((2S,3S)-1-((3aS,6S,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)benzamideN-((2S,3S)-1-((3aS,6S,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)-4-(1-(2-methoxyethyl)piperazin-4-yl)benzamide4-(4-cyclopropylpiperazin-1-yl)-N-((2S,3S)-1-((3aS,6S,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)benzamide4-(4-cyclobutylpiperazin-1-yl)-N-((2S,3S)-1-((3aS,6S,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)benzamideN-((2S,3S)-1-((3aS,6S,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)-4-(1-methylpiperidin-4-yl)benzamide4-(1-ethylpiperidin-4-yl)-N-((2S,3S)-1-((3aS,6S,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)benzamideN-((2S,3S)-1-((3aS,6S,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)-4-(1-propylpiperidin-4-yl)benzamide4-(1-isopropylpiperidin-4-yl)-N-((2S,3S)-1-((3aS,6S,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)benzamideN-((2S,3S)-1-((3aS,6S,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)-4-(1-(2-methoxyethyl)piperidin-4-yl)benzamide4-(1-cyclopropylpiperidin-4-yl)-N-((2S,3S)-1-((3aS,6S,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)benzamide4-(1-cyclobutylpiperidin-4-yl)-N-((2S,3S)-1-((3aS,6S,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)benzamideN—((S)-1-((3aS,6S,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxobutan-2-yl)-4-(4-methylpiperazin-1-yl)benzamide4-(4-ethylpiperazin-1-yl)-N—((S)-1-((3aS,6S,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxobutan-2-yl)benzamideN—((S)-1-((3aS,6S,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxobutan-2-yl)-4-(4-propylpiperazin-1-yl)benzamide4-(4-isopropylpiperazin-1-yl)-N—((S)-1-((3aS,6S,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxobutan-2-yl)benzamideN—((S)-1-((3aS,6S,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxobutan-2-yl)-4-(4-(2-methoxyethyl)piperazin-1-yl)benzamide4-(4-cyclopropylpiperazin-1-yl)-N—((S)-1-((3aS,6S,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxobutan-2-yl)benzamide4-(4-cyclobutylpiperazin-1-yl)-N—((S)-1-((3aS,6S,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxobutan-2-yl)benzamideN—((S)-1-((3aS,6S,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxobutan-2-yl)-4-(1-propylpiperidin-4-yl)benzamide4-(1-cyclopropylpiperidin-4-yl)-N—((S)-1-((3aS,6S,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxobutan-2-yl)benzamide4-(1-cyclobutylpiperidin-4-yl)-N—((S)-1-((3aS,6S,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxobutan-2-yl)benzamideN—((S)-1-cyclopentyl-2-((3aS,6S,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-methylpiperazin-1-yl)benzamideN—((S)-1-cyclopentyl-2-((3aS,6S,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-ethylpiperazin-1-yl)benzamideN—((S)-1-cyclopentyl-2-((3aS,6S,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-propylpiperazin-1-yl)benzamideN—((S)-1-cyclopentyl-2-((3aS,6S,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-isopropylpiperazin-1-yl)benzamideN—((S)-1-cyclopentyl-2-((3aS,6S,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-(2-methoxyethyl)piperazin-1-yl)benzamideN—((S)-1-cyclopentyl-2-((3aS,6S,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-cyclopropylpiperazin-1-yl)benzamide4-(4-cyclobutylpiperazin-1-yl)-N—((S)-1-cyclopentyl-2-((3aS,6S,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)benzamideN—((S)-1-cyclopentyl-2-((3aS,6S,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(1-propylpiperidin-4-yl)benzamideN—((S)-1-cyclopentyl-2-((3aS,6S,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(1-cyclopropylpiperidin-4-yl)benzamide4-(1-cyclobutylpiperidin-4-yl)-N—((S)-1-cyclopentyl-2-((3aS,6S,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)benzamideN—((S)-1-cyclohexyl-2-((3aS,6S,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-methylpiperazin-1-yl)benzamideN—((S)-1-cyclohexyl-2-((3aS,6S,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-ethylpiperazin-1-yl)benzamideN—((S)-1-cyclohexyl-2-((3aS,6S,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-propylpiperazin-1-yl)benzamideN—((S)-1-cyclohexyl-2-((3aS,6S,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-isopropylpiperazin-1-yl)benzamideN—((S)-1-cyclohexyl-2-((3aS,6S,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-(2-methoxyethyl)piperazin-1-yl)benzamideN—((S)-1-cyclohexyl-2-((3aS,6S,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-cyclopropylpiperazin-1-yl)benzamide4-(4-cyclobutylpiperazin-1-yl)-N—((S)-1-cyclohexyl-2-((3aS,6S,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)benzamideN—((S)-1-cyclohexyl-2-((3aS,6S,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(1-methylpiperidin-4-yl)benzamideN—((S)-1-cyclohexyl-2-((3aS,6S,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(1-ethylpiperidin-4-yl)benzamideN—((S)-1-cyclohexyl-2-((3aS,6S,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(1-propylpiperidin-4-yl)benzamideN—((S)-1-cyclohexyl-2-((3aS,6S,6aS)-6-methoxy-3-oxodihydro-2-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(1-isopropylpiperidin-4-yl)benzamideN—((S)-1-cyclohexyl-2-((3aS,6S,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(1-(2-methoxyethyl)piperidin-4-yl)benzamideN—((S)-1-cyclohexyl-2-((3aS,6S,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(1-cyclopropylpiperidin-4-yl)benzamide4-(1-cyclobutylpiperidin-4-yl)-N—((S)-1-cyclohexyl-2-((3aS,6S,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)benzamideN—((S)-1-((3aS,6S,6aS)-6-ethoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)-4-(4-methylpiperazin-1-yl)benzamideN—((S)-1-((3aS,6S,6aS)-6-ethoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)-4-(4-ethylpiperazin-1-yl)benzamideN—((S)-1-((3aS,6S,6aS)-6-ethoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)-4-(4-propylpiperazin-1-yl)benzamideN—((S)-1-((3aS,6S,6aS)-6-ethoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)-4-(4-isopropylpiperazin-1-yl)benzamideN—((S)-1-((3aS,6S,6aS)-6-ethoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)-4-(4-(2-methoxyethyl)piperazin-1-yl)benzamide4-(4-cyclopropylpiperazin-1-yl)-N—((S)-1-((3aS,6S,6aS)-6-ethoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)benzamide4-(4-cyclobutylpiperazin-1-yl)-N—((S)-1-((3aS,6S,6aS)-6-ethoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)benzamideN—((S)-1-((3aS,6S,6aS)-6-ethoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)-4-(1-propylpiperidin-4-yl)benzamideN—((S)-1-((3aS,6S,6aS)-6-ethoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)-4-(1-isopropylpiperidin-4-yl)benzamideN—((S)-1-((3aS,6S,6aS)-6-ethoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)-4-(1-(2-methoxyethyl)piperidin-4-yl)benzamide4-(1-cyclopropylpiperidin-4-yl)-N—((S)-1-((3aS,6S,6aS)-6-ethoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)benzamide4-(1-cyclobutylpiperidin-4-yl)-N—((S)-1-((3aS,6S,6aS)-6-ethoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)benzamideN—((S)-1-((3aS,6S,6aS)-6-ethoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)-4-(4-methylpiperazin-1-yl)benzamideN—((S)-1-((3aS,6S,6aS)-6-ethoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)-4-(4-ethylpiperazin-1-yl)benzamideN—((S)-1-((3aS,6S,6aS)-6-ethoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)-4-(4-propylpiperazin-1-yl)benzamideN—((S)-1-((3aS,6S,6aS)-6-ethoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)-4-(4-isopropylpiperazin-1-yl)benzamideN—((S)-1-((3aS,6S,6aS)-6-ethoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)-4-(4-(2-methoxyethyl)piperazin-1-yl)benzamide4-(4-cyclopropylpiperazin-1-yl)-N—((S)-1-((3aS,6S,6aS)-6-ethoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)benzamide4-(4-cyclobutylpiperazin-1-yl)-N—((S)-1-((3aS,6S,6aS)-6-ethoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)benzamideN—((S)-1-((3aS,6S,6aS)-6-ethoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)-4-(1-propylpiperidin-4-yl)benzamide4-(1-cyclopropylpiperidin-4-yl)-N—((S)-1-((3aS,6S,6aS)-6-ethoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)benzamide4-(1-cyclobutylpiperidin-4-yl)-N—((S)-1-((3aS,6S,6aS)-6-ethoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)benzamideN-((2S,3S)-1-((3aS,6S,6aS)-6-ethoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)-4-(4-methylpiperazin-1-yl)benzamideN-((2S,3S)-1-((3aS,6S,6aS)-6-ethoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)-4-(4-ethylpiperazin-1-yl)benzamideN-((2S,3S)-1-((3aS,6S,6aS)-6-ethoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)-4-(4-propylpiperazin-1-yl)benzamideN-((2S,3S)-1-((3aS,6S,6aS)-6-ethoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)-4-(4-isopropylpiperazin-1-yl)benzamideN-((2S,3S)-1-((3aS,6S,6aS)-6-ethoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)-4-(4-(2-methoxyethyl)piperazin-1-yl)benzamide4-(4-cyclopropylpiperazin-1-yl)-N-((2S,3S)-1-((3aS,6S,6aS)-6-ethoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)benzamide4-(4-cyclobutylpiperazin-1-yl)-N-((2S,3S)-1-((3aS,6S,6aS)-6-ethoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)benzamideN-((2S,3S)-1-((3aS,6S,6aS)-6-ethoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)-4-(1-methylpiperidin-4-yl)benzamideN-((2S,3S)-1-((3aS,6S,6aS)-6-ethoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)-4-(1-ethylpiperidin-4-yl)benzamideN-((2S,3S)-1-((3aS,6S,6aS)-6-ethoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)-4-(1-propylpiperidin-4-yl)benzamideN-((2S,3S)-1-((3aS,6S,6aS)-6-ethoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)-4-(1-isopropylpiperidin-4-yl)benzamideN-((2S,3S)-1-((3aS,6S,6aS)-6-ethoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)-4-(1-(2-methoxyethyl)piperidin-4-yl)benzamide4-(1-cyclopropylpiperidin-4-yl)-N-((2S,3S)-1-((3aS,6S,6aS)-6-ethoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)benzamide4-(1-cyclobutylpiperidin-4-yl)-N-((2S,3S)-1-((3aS,6S,6aS)-6-ethoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)benzamideN—((S)-1-((3aS,6S,6aS)-6-ethoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxobutan-2-yl)-4-(4-methylpiperazin-1-yl)benzamideN—((S)-1-((3aS,6S,6aS)-6-ethoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxobutan-2-yl)-4-(4-ethylpiperazin-1-yl)benzamideN—((S)-1-((3aS,6S,6aS)-6-ethoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxobutan-2-yl)-4-(4-propylpiperazin-1-yl)benzamideN—((S)-1-((3aS,6S,6aS)-6-ethoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxobutan-2-yl)-4-(4-isopropylpiperazin-1-yl)benzamideN—((S)-1-((3aS,6S,6aS)-6-ethoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxobutan-2-yl)-4-(4-(2-methoxyethyl)piperazin-1-yl)benzamide4-(4-cyclopropylpiperazin-1-yl)-N—((S)-1-((3aS,6S,6aS)-6-ethoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxobutan-2-yl)benzamide4-(4-cyclobutylpiperazin-1-yl)-N—((S)-1-((3aS,6S,6aS)-6-ethoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxobutan-2-yl)benzamideN—((S)-1-((3aS,6S,6aS)-6-ethoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxobutan-2-yl)-4-(1-propylpiperidin-4-yl)benzamide4-(1-cyclopropylpiperidin-4-yl)-N—((S)-1-((3aS,6S,6aS)-6-ethoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxobutan-2-yl)benzamide4-(1-cyclobutylpiperidin-4-yl)-N—((S)-1-((3aS,6S,6aS)-6-ethoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxobutan-2-yl)benzamideN—((S)-1-cyclopentyl-2-((3aS,6S,6aS)-6-ethoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-methylpiperazin-1-yl)benzamideN—((S)-1-cyclopentyl-2-((3aS,6S,6aS)-6-ethoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-ethylpiperazin-1-yl)benzamideN—((S)-1-cyclopentyl-2-((3aS,6S,6aS)-6-ethoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-propylpiperazin-1-yl)benzamideN—((S)-1-cyclopentyl-2-((3aS,6S,6aS)-6-ethoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-isopropylpiperazin-1-yl)benzamideN—((S)-1-cyclopentyl-2-((3aS,6S,6aS)-6-ethoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-(2-methoxyethyl)piperazin-1-yl)benzamideN—((S)-1-cyclopentyl-2-((3aS,6S,6aS)-6-ethoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-cyclopropylpiperazin-1-yl)benzamide4-(4-cyclobutylpiperazin-1-yl)-N—((S)-1-cyclopentyl-2-((3aS,6S,6aS)-6-ethoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)benzamideN—((S)-1-cyclopentyl-2-((3aS,6S,6aS)-6-ethoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(1-methylpiperidin-4-yl)benzamideN—((S)-1-cyclopentyl-2-((3aS,6S,6aS)-6-ethoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(1-ethylpiperidin-4-yl)benzamideN—((S)-1-cyclopentyl-2-((3aS,6S,6aS)-6-ethoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(1-propylpiperidin-4-yl)benzamideN—((S)-1-cyclopentyl-2-((3aS,6S,6aS)-6-ethoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(1-isopropylpiperidin-4-yl)benzamideN—((S)-1-cyclopentyl-2-((3aS,6S,6aS)-6-ethoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(1-(2-methoxyethyl)piperidin-4-yl)benzamideN—((S)-1-cyclopentyl-2-((3aS,6S,6aS)-6-ethoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(1-cyclopropylpiperidin-4-yl)benzamide4-(1-cyclobutylpiperidin-4-yl)-N—((S)-1-cyclopentyl-2-((3aS,6S,6aS)-6-ethoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)benzamideN—((S)-1-cyclohexyl-2-((3aS,6S,6aS)-6-ethoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-methylpiperazin-1-yl)benzamideN—((S)-1-cyclohexyl-2-((3aS,6S,6aS)-6-ethoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-ethylpiperazin-1-yl)benzamideN—((S)-1-cyclohexyl-2-((3aS,6S,6aS)-6-ethoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-propylpiperazin-1-yl)benzamideN—((S)-1-cyclohexyl-2-((3aS,6S,6aS)-6-ethoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-isopropylpiperazin-1-yl)benzamideN—((S)-1-cyclohexyl-2-((3aS,6S,6aS)-6-ethoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-(2-methoxyethyl)piperazin-1-yl)benzamideN—((S)-1-cyclohexyl-2-((3aS,6S,6aS)-6-ethoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-cyclopropylpiperazin-1-yl)benzamide4-(4-cyclobutylpiperazin-1-yl)-N—((S)-1-cyclohexyl-2-((3aS,6S,6aS)-6-ethoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)benzamideN—((S)-1-cyclohexyl-2-((3aS,6S,6aS)-6-ethoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(1-methylpiperidin-4-yl)benzamideN—((S)-1-cyclohexyl-2-((3aS,6S,6aS)-6-ethoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(1-ethylpiperidin-4-yl)benzamideN—((S)-1-cyclohexyl-2-((3aS,6S,6aS)-6-ethoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(1-propylpiperidin-4-yl)benzamideN—((S)-1-cyclohexyl-2-((3aS,6S,6aS)-6-ethoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(1-isopropylpiperidin-4-yl)benzamideN—((S)-1-cyclohexyl-2-((3aS,6S,6aS)-6-ethoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(1-(2-methoxyethyl)piperidin-4-yl)benzamideN—((S)-1-cyclohexyl-2-((3aS,6S,6aS)-6-ethoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(1-cyclopropylpiperidin-4-yl)benzamide4-(1-cyclobutylpiperidin-4-yl)-N—((S)-1-cyclohexyl-2-((3aS,6S,6aS)-6-ethoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)benzamideN—((S)-1-((3aS,6S,6aR)-6-amino-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)-4-(1-propylpiperazin-1-yl)benzamideN—((S)-1-((3aS,6S,6aR)-6-amino-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)-4-(1-cyclopropylpiperazin-1-yl)benzamideN—((S)-1-((3aS,6S,6aR)-6-amino-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)-4-(1-cyclobutylpiperazin-1-yl)benzamideN-((2S,3S)-1-((3aS,6S,6aR)-6-amino-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)-4-(4-ethylpiperazin-1-yl)benzamideN-((2S,3S)-1-((3aS,6S,6aR)-6-amino-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)-4-(4-propylpiperazin-1-yl)benzamideN-((2S,3S)-1-((3aS,6S,6aR)-6-amino-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)-4-(4-isopropylpiperazin-1-yl)benzamideN-((2S,3S)-1-((3aS,6S,6aR)-6-amino-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)-4-(4-cyclopropylpiperazin-1-yl)benzamideN-((2S,3S)-1-((3aS,6S,6aR)-6-amino-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)-4-(4-cyclobutylpiperazin-1-yl)benzamideN—((S)-1-((3aS,6S,6aR)-6-amino-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxobutan-2-yl)-4-(4-propylpiperazin-1-yl)benzamideN—((S)-1-((3aS,6S,6aR)-6-amino-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-di-methyl-1-oxobutan-2-yl)-4-(4-cyclopropylpiperazin-1-yl)benzamideN—((S)-1-((3aS,6S,6aR)-6-amino-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-di-methyl-1-oxobutan-2-yl)-4-(4-cyclobutylpiperazin-1-yl)benzamideN—((S)-2-((3aS,6S,6aR)-6-amino-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-1-cyclopentyl-2-oxoethyl)-4-(4-propylpiperazin-1-yl)benzamideN—((S)-2-((3aS,6S,6aR)-6-amino-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-1-cyclopentyl-2-oxoethyl)-4-(4-cyclopropylpiperazin-1-yl)benzamideN—((S)-2-((3aS,6S,6aR)-6-amino-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-1-cyclopentyl-2-oxoethyl)-4-(4-cyclobutylpiperazin-1-yl)benzamideN—((S)-2-((3aS,6S,6aR)-6-amino-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-1-cyclohexyl-2-oxoethyl)-4-(4-ethylpiperazin-1-yl)benzamideN—((S)-2-((3aS,6S,6aR)-6-amino-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-1-cyclohexyl-2-oxoethyl)-4-(propylpiperazin-1-yl)benzamideN—((S)-2-((3aS,6S,6aR)-6-amino-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-1-cyclohexyl-2-oxoethyl)-4-(isopropylpiperazin-1-yl)benzamideN—((S)-2-((3aS,6S,6aR)-6-amino-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-1-cyclohexyl-2-oxoethyl)-4-(cyclopropylpiperazin-1-yl)benzamideN—((S)-2-((3aS,6S,6aR)-6-amino-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-1-cyclohexyl-2-oxoethyl)-4-(cyclobutylpiperazin-1-yl)benzamideN—((S)-1-((3aS,6S,6aR)-6-(methylamino)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)-4-(4-propylpiperazin-1-yl)benzamide4-(4-cyclopropylpiperazin-1-yl)-N—((S)-1-((3aS,6S,6aR)-6-(methylamino)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)benzamide4-(4-cyclobutylpiperazin-1-yl)-N—((S)-1-((3aS,6S,6aR)-6-(methylamino)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)benzamide4-(1-cyclopropylpiperidin-4-yl)-N—((S)-1-((3aS,6S,6aR)-6-(methylamino)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)benzamide4-(1-cyclobutylpiperidin-4-yl)-N—((S)-1-((3aS,6S,6aR)-6-(methylamino)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)benzamideN—((S)-1-((3aS,6S,6aR)-6-(methylamino)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)-4-(4-propylpiperazin-1-yl)benzamide4-(4-cyclopropylpiperazin-1-yl)-N—((S)-1-((3aS,6S,6aR)-6-(methylamino)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)benzamide4-(4-cyclobutylpiperazin-1-yl)-N—((S)-1-((3aS,6S,6aR)-6-(methylamino)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)benzamide4-(4-ethylpiperazin-1-yl)-N-((2S,3S)-1-((3aS,6S,6aR)-6-(methylamino)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)benzamideN-((2S,3S)-1-((3aS,6S,6aR)-6-(methylamino)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)-4-(4-propylpiperazin-1-yl)benzamide4-(4-isopropylpiperazin-1-yl-N-((2S,3S)-1-((3aS,6S,6aR)-6-(methylamino)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)-)benzamide4-(4-(2-methoxyethyl)piperazin-1-yl)-N-((2S,3S)-1-((3aS,6S,6aR)-6-(methylamino)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)benzamide4-(4-cyclopropylpiperazin-1-yl)-N-((2S,3S)-1-((3aS,6S,6aR)-6-(methylamino)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)benzamide4-(4-cyclobutylpiperazin-1-yl)-N-((2S,3S)-1-((3aS,6S,6aR)-6-(methylamino)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)benzamideN-((2S,3S)-1-((3aS,6S,6aR)-6-(methylamino)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)-4-(1-propylpiperidin-4-yl)benzamide4-(1-isopropylpiperidin-4-yl)-N-((2S,3S)-1-((3aS,6S,6aR)-6-(methylamino)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)benzamide4-(1-cyclopropylpiperidin-4-yl)-N-((2S,3S)-1-((3aS,6S,6aR)-6-(methylamino)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)benzamide4-(1-cyclobutylpiperidin-4-yl)-N-((2S,3S)-1-((3aS,6S,6aR)-6-(methylamino)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)benzamideN—((S)-1-((3aS,6S,6aR)-6-(methylamino)-3-oxodihydro-2H-furo[3,2-pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxobutan-2-yl)-4-(4-propylpiperazin-1-yl)benzamide4-(4-cyclopropylpiperazin-1-yl)-N—((S)-1-((3aS,6S,6aR)-6-(methylamino)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxobutan-2-yl)benzamide4-(4-cyclobutylpiperazin-1-yl)-N—((S)-1-((3aS,6S,6aR)-6-(methylamino)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxobutan-2-yl)benzamideN—((S)-1-((3aS,6S,6aR)-6-(methylamino)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxobutan-2-yl)-4-(1-propylpiperidin-4-yl)benzamide4-(1-cyclopropylpiperidin-4-yl)-N—((S)-1-((3aS,6S,6aR)-6-(methylamino)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3′3-di-methyl-1-oxobutan-2-yl)benzamide4-(1-cyclobutylpiperidin-4-yl)-N—((S)-1-((3aS,6S,6aR)-6-(methylamino)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-di-methyl-1-oxobutan-2-yl)benzamideN—((S)-1-cyclopentyl-2-((3aS,6S,6aR)-6-(methylamino)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-propylpiperazin-1-yl)benzamideN—((S)-1-cyclopentyl-2-((3aS,6S,6aR)-6-(methylamino)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-cyclopropylpiperazin-1-yl)benzamide4-(4-cyclobutylpiperazin-1-yl)-N—((S)-1-cyclopentyl-2-((3aS,6S,6aR)-6-(methylamino)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)benzamideN—((S)-1-cyclopentyl-2-((3aS,6S,6aR)-6-(methylamino)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(1-propylpiperidin-4-yl)benzamideN—((S)-1-cyclopentyl-2-((3aS,6S,6aR)-6-(methylamino)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(1-cyclopropylpiperidin-4-yl)benzamide4-(1-cyclobutylpiperidin-4-yl)-N—((S)-1-cyclopentyl-2-((3aS,6S,6aR)-6-(methylamino)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)benzamideN—((S)-1-cyclohexyl-2-((3aS,6S,6aR)-6-(methylamino)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-ethylpiperazin-1-yl)benzamideN—((S)-1-cyclohexyl-2-((3aS,6S,6aR)-6-(methylamino)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-propylpiperazin-1-yl)benzamideN—((S)-1-cyclohexyl-2-((3aS,6S,6aR)-6-(methylamino)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-isopropylpiperazin-1-yl)benzamideN—((S)-1-cyclohexyl-2-((3aS,6S,6aR)-6-(methylamino)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-cyclopropylpiperazin-1-yl)benzamide4-(4-cyclobutylpiperazin-1-yl)-N—((S)-1-cyclohexyl-2-((3aS,6S,6aR)-6-(methylamino)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)benzamideN—((S)-1-cyclohexyl-2-((3aS,6S,6aR)-6-(methylamino)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(1-propylpiperidin-4-yl)benzamideN—((S)-1-cyclohexyl-2-((3aS,6S,6aR)-6-(methylamino)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(1-cyclopropylpiperidin-4-yl)benzamide4-(1-cyclobutylpiperidin-4-yl)-N—((S)-1-cyclohexyl-2-((3aS,6S,6aR)-6-(methylamino)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)benzamide4-(4-methylpiperazin-1-yl)-N—((S)-1-((3aS,6S,6aS)-6-(methylthio)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)benzamide4-(4-ethylpiperazin-1-yl)-N—((S)-1-((3aS,6S,6aS)-6-(methylthio)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)benzamideN—((S)-1-((3aS,6S,6aS)-6-(methylthio)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)-4-(4-propylpiperazin-1-yl)benzamide4-(4-isopropylpiperazin-1-yl)-N—((S)-1-((3aS,6S,6aS)-6-(methylthio)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)benzamide4-(4-(2-methoxyethyl)piperazin-1-yl)-N—((S)-1-((3aS,6S,6aS)-6-(methylthio)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)benzamide4-(4-cyclopropylpiperazin-1-yl)-N—((S)-1-((3aS,6S,6aS)-6-(methylthio)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)benzamide4-(4-cyclobutylpiperazin-1-yl)-N—((S)-1-((3aS,6S,6aS)-6-(methylthio)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)benzamide4-(1-ethylpiperidin-4-yl)-N—((S)-1-((3aS,6S,6aS)-6-(methylthio)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)benzamideN—((S)-1-((3aS,6S,6aS)-6-(methylthio)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)-4-(1-propylpiperidin-4-yl)benzamide4-(1-isopropylpiperidin-4-yl)-N—((S)-1-((3aS,6S,6aS)-6-(methylthio)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)benzamide4-(1-(2-methoxyethyl)piperidin-4-yl)-N—((S)-1-((3aS,6S,6aS)-6-(methylthio)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)benzamide4-(1-cyclopropylpiperidin-4-yl)-N—((S)-1-((3aS,6S,6aS)-6-(methylthio)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)benzamide4-(1-cyclobutylpiperidin-4-yl)-N—((S)-1-((3aS,6S,6aS)-6-(methylthio)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)benzamide4-(4-methylpiperazin-1-yl)-N—((S)-1-((3aS,6S,6aS)-6-(methylthio)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)benzamide4-(4-ethylpiperazin-1-yl)-N—((S)-1-((3aS,6S,6aS)-6-(methylthio)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)benzamideN—((S)-1-((3aS,6S,6aS)-6-(methylthio)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)-4-(4-propylpiperazin-1-yl)benzamide4-(4-isopropylpiperazin-1-yl)-N—((S)-1-((3aS,6S,6aS)-6-(methylthio)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)benzamide4-(4-(2-methoxyethyl)piperazin-1-yl)-N—((S)-1-((3aS,6S,6aS)-6-(methylthio)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)benzamide4-(4-cyclopropylpiperazin-1-yl)-N—((S)-1-((3aS,6S,6aS)-6-(methylthio)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)benzamide4-(4-cyclobutylpiperazin-1-yl)-N—((S)-1-((3aS,6S,6aS)-6-(methylthio)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)benzamideN—((S)-1-((3aS,6S,6aS)-6-(methylthio)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)-4-(1-propylpiperidin-4-yl)benzamide4-(1-isopropylpiperidin-4-yl)-N—((S)-1-((3aS,6S,6aS)-6-(methylthio)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)benzamide4-(1-cyclopropylpiperidin-4-yl)-N—((S)-1-((3aS,6S,6aS)-6-(methylthio)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)benzamide4-(1-cyclobutylpiperidin-4-yl)-N—((S)-1-((3aS,6S,6aS)-6-(methylthio)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)benzamide4-(4-methylpiperazin-1-yl)-N-((2S,3S)-1-((3aS,6S,6aS)-6-(methylthio)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)benzamide4-(4-ethylpiperazin-1-yl)-N-((2S,3S)-1-((3aS,6S,6aS)-6-(methylthio)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)benzamideN-((2S,3S)-1-((3aS,6S,6aS)-6-(methylthio)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)-4-(4-propylpiperazin-1-yl)benzamide4-(4-isopropylpiperazin-1-yl)-N-((2S,3S)-1-((3aS,6S,6aS)-6-(methylthio)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)benzamide4-(4-(2-methoxyethyl)piperazin-1-yl)-N-((2S,3S)-1-((3aS,6S,6aS)-6-(methylthio)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)benzamide4-(4-cyclopropylpiperazin-1-yl)-N-((2S,3S)-1-((3aS,6S,6aS)-6-(methylthio)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)benzamide4-(4-cyclobutylpiperazin-1-yl)-N-((2S,3S)-1-((3aS,6S,6aS)-6-(methylthio)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)benzamide4-(1-methylpiperidin-4-yl)-N-((2S,3S)-1-((3aS,6S,6aS)-6-(methylthio)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)benzamide4-(1-ethylpiperidin-4-yl)-N-((2S,3S)-1-((3aS,6S,6aS)-6-(methylthio)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)benzamideN-((2S,3S)-1-((3aS,6S,6aS)-6-(methylthio)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)-4-(1-propylpiperidin-4-yl)benzamide4-(1-isopropylpiperidin-4-yl)-N-((2S,3S)-1-((3aS,6S,6aS)-6-(methylthio)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)benzamide4-(1-(2-methoxyethyl)piperidin-4-yl)-N-((2S,3S)-1-((3aS,6S,6aS)-6-(methylthio)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)benzamide4-(1-cyclopropylpiperidin-4-yl)-N-((2S,3S)-1-((3aS,6S,6aS)-6-(methylthio)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)benzamide4-(1-cyclobutylpiperidin-4-yl)-N-((2S,3S)-1-((3aS,6S,6aS)-6-(methylthio)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)benzamide4-(4-methylpiperazin-1-yl)-N—((S)-1-((3aS,6S,6aS)-6-(methylthio)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxobutan-2-yl)benzamide4-(4-ethylpiperazin-1-yl)-N—((S)-1-((3aS,6S,6aS)-6-(methylthio)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxobutan-2-yl)benzamideN—((S)-1-((3aS,6S,6aS)-6-(methylthio)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxobutan-2-yl)-4-(4-propylpiperazin-1-yl)benzamide4-(4-isopropylpiperazin-1-yl)-N—((S)-1-((3aS,6S,6aS)-6-(methylthio)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxobutan-2-yl)benzamide4-(4-(2-methoxyethyl)piperazin-1-yl)-N—((S)-1-((3aS,6S,6aS)-6-(methylthio)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-di-methyl-1-oxobutan-2-yl)benzamide4-(4-cyclopropylpiperazin-1-yl)-N—((S)-1-((3aS,6S,6aS)-6-(methylthio)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxobutan-2-yl)benzamide4-(4-cyclobutylpiperazin-1-yl)-N—((S)-1-((3aS,6S,6aS)-6-(methylthio)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxobutan-2-yl)benzamide4-(1-ethylpiperidin-4-yl)-N—((S)-1-((3aS,6S,6aS)-6-(methylthio)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxobutan-2-yl)benzamideN—((S)-1-((3aS,6S,6aS)-6-(methylthio)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxobutan-2-yl)-4-(1-propylpiperidin-4-yl)benzamide4-(1-isopropylpiperidin-4-yl)-N—((S)-1-((3aS,6S,6aS)-6-(methylthio)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxobutan-2-yl)benzamide4-(1-cyclopropylpiperidin-4-yl)-N—((S)-1-((3aS,6S,6aS)-6-(methylthio)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxobutan-2-yl)benzamide4-(1-cyclobutylpiperidin-4-yl)-N—((S)-1-((3aS,6S,6aS)-6-(methylthio)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxobutan-2-yl)benzamideN—((S)-1-cyclopentyl-2-((3aS,6S,6aS)-6-(methylthio)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-methylpiperazin-1-yl)benzamideN—((S)-1-cyclopentyl-2-((3aS,6S,6aS)-6-(methylthio)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-ethylpiperazin-1-yl)benzamideN—((S)-1-cyclopentyl-2-((3aS,6S,6aS)-6-(methylthio)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-propylpiperazin-1-yl)benzamideN—((S)-1-cyclopentyl-2-((3aS,6S,6aS)-6-(methylthio)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-isopropylpiperazin-1-yl)benzamideN—((S)-1-cyclopentyl-2-((3aS,6S,6aS)-6-(methylthio)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-(2-methoxyethyl)piperazin-1-yl)benzamideN—((S)-1-cyclopentyl-2-((3aS,6S,6aS)-6-(methylthio)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-cyclopropylpiperazin-1-yl)benzamide4-(4-cyclobutylpiperazin-1-yl)-N—((S)-1-cyclopentyl-2-((3aS,6S,6aS)-6-(methylthio)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)benzamideN—((S)-1-cyclopentyl-2-((3aS,6S,6aS)-6-(methylthio)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(1-methylpiperidin-4-yl)benzamideN—((S)-1-cyclopentyl-2-((3aS,6S,6aS)-6-(methylthio)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(1-ethylpiperidin-4-yl)benzamideN—((S)-1-cyclopentyl-2-((3aS,6S,6aS)-6-(methylthio)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(1-propylpiperidin-4-yl)benzamideN—((S)-1-cyclopentyl-2-((3aS,6S,6aS)-6-(methylthio)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(1-isopropylpiperidin-4-yl)benzamideN—((S)-1-cyclopentyl-2-((3aS,6S,6aS)-6-(methylthio)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(1-(2-methoxyethyl)piperidin-4-yl)benzamideN—((S)-1-cyclopentyl-2-((3aS,6S,6aS)-6-(methylthio)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(1-cyclopropylpiperidin-4-yl)benzamide4-(1-cyclobutylpiperidin-4-yl)-N—((S)-1-cyclopentyl-2-((3aS,6S,6aS)-6-(methylthio)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)benzamideN—((S)-1-cyclohexyl-2-((3aS,6S,6aS)-6-(methylthio)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-methylpiperazin-1-yl)benzamideN—((S)-1-cyclohexyl-2-((3aS,6S,6aS)-6-(methylthio)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-ethylpiperazin-1-yl)benzamideN—((S)-1-cyclohexyl-2-((3aS,6S,6aS)-6-(methylthio)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-propylpiperazin-1-yl)benzamideN—((S)-1-cyclohexyl-2-((3aS,6S,6aS)-6-(methylthio)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-isopropylpiperazin-1-yl)benzamideN—((S)-1-cyclohexyl-2-((3aS,6S,6aS)-6-(methylthio)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-(2-methoxyethyl)piperazin-1-yl)benzamideN—((S)-1-cyclohexyl-2-((3aS,6S,6aS)-6-(methylthio)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-cyclopropylpiperazin-1-yl)benzamide4-(4-cyclobutylpiperazin-1-yl)-N—((S)-1-cyclohexyl-2-((3aS,6S,6aS)-6-(methylthio)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)benzamideN—((S)-1-cyclohexyl-2-((3aS,6S,6aS)-6-(methylthio)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(1-methylpiperidin-4-yl)benzamideN—((S)-1-cyclohexyl-2-((3aS,6S,6aS)-6-(methylthio)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(1-ethylpiperidin-4-yl)benzamideN—((S)-1-cyclohexyl-2-((3aS,6S,6aS)-6-(methylthio)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(1-propylpiperidin-4-yl)benzamideN—((S)-1-cyclohexyl-2-((3aS,6S,6aS)-6-(methylthio)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(1-isopropylpiperidin-4-yl)benzamideN—((S)-1-cyclohexyl-2-((3aS,6S,6aS)-6-(methylthio)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(1-(2-methoxyethyl)piperidin-4-yl)benzamideN—((S)-1-cyclohexyl-2-((3aS,6S,6aS)-6-(methylthio)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(1-cyclopropylpiperidin-4-yl)benzamide4-(1-cyclobutylpiperidin-4-yl)-N—((S)-1-cyclohexyl-2-((3aS,6S,6aS)-6-(methylthio)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)benzamideN—((S)-1-((3aS,6S,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)-4-(4-methylpiperazin-1-yl)benzamideN—((S)-1-((3aS,6S,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)-4-(4-ethylpiperazin-1-yl)benzamideN—((S)-1-((3aS,6S,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)-4-(4-propylpiperazin-1-yl)benzamideN—((S)-1-((3aS,6S,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)-4-(4-isopropylpiperazin-1-yl)benzamideN—((S)-1-((3aS,6S,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)-4-(4-(2-methoxyethyl)piperazin-1-yl)benzamideN—((S)-1-((3aS,6S,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)-4-(4-cyclopropylpiperazin-1-yl)benzamideN—((S)-1-((3aS,6S,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)-4-(4-cyclobutylpiperazin-1-yl)benzamideN—((S)-1-((3aS,6S,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)-4-(1-propylpiperidin-4-yl)benzamideN—((S)-1-((3aS,6S,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)-4-(1-isopropylpiperidin-4-yl)benzamideN—((S)-1-((3aS,6S,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)-4-(1-(2-methoxyethyl)piperidin-4-yl)benzamideN—((S)-1-((3aS,6S,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)-4-(1-cyclopropylpiperidin-4-yl)benzamideN—((S)-1-((3aS,6S,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)-4-(1-cyclobutylpiperidin-4-yl)benzamideN—((S)-1-((3aS,6S,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)-4-(4-methylpiperazin-1-yl)benzamideN—((S)-1-((3aS,6S,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)-4-(4-ethylpiperazin-1-yl)benzamideN—((S)-1-((3aS,6S,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)-4-(4-propylpiperazin-1-yl)benzamideN—((S)-1-((3aS,6S,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)-4-(4-isopropylpiperazin-1-yl)benzamideN—((S)-1-((3aS,6S,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)-4-(4-(2-methoxyethyl)piperazin-1-yl)benzamideN—((S)-1-((3aS,6S,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)-4-(4-cyclopropylpiperazin-1-yl)benzamideN—((S)-1-((3aS,6S,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)-4-(4-cyclobutylpiperazin-1-yl)benzamideN—((S)-1-((3aS,6S,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)-4-(1-propylpiperidin-4-yl)benzamideN—((S)-1-((3aS,6S,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)-4-(1-cyclopropylpiperidin-4-yl)benzamideN—((S)-1-((3aS,6S,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)-4-(1-cyclobutylpiperidin-4-yl)benzamideN-((2S,3S)-1-((3aS,6S,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)-4-(4-methylpiperazin-1-yl)benzamideN-((2S,3S)-1-((3aS,6S,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)-4-(4-ethylpiperazin-1-yl)benzamideN-((2S,3S)-1-((3aS,6S,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)-4-(4-propylpiperazin-1-yl)benzamideN-((2S,3S)-1-((3aS,6S,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)-4-(4-isopropylpiperazin-1-yl)benzamideN-((2S,3S)-1-((3aS,6S,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)-4-(4-(2-methoxyethyl)piperazin-1-yl)benzamideN-((2S,3S)-1-((3aS,6S,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)-4-(4-cyclopropylpiperazin-1-yl)benzamideN-((2S,3S)-1-((3aS,6S,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)-4-(4-cyclobutylpiperazin-1-yl)benzamideN-((2S,3S)-1-((3aS,6S,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)-4-(1-methylpiperidin-4-yl)benzamideN-((2S,3S)-1-((3aS,6S,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)-4-(1-ethylpiperidin-4-yl)benzamideN-((2S,3S)-1-((3aS,6S,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)-4-(1-propylpiperidin-4-yl)benzamideN-((2S,3S)-1-((3aS,6S,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)-4-(1-isopropylpiperidin-4-yl)benzamideN-((2S,3S)-1-((3aS,6S,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)-4-(1-(2-methoxyethyl)piperidin-4-yl)benzamideN-((2S,3S)-1-((3aS,6S,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)-4-(1-cyclopropylpiperidin-4-yl)benzamideN-((2S,3S)-1-((3aS,6S,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)-4-(1-cyclobutylpiperidin-4-yl)benzamideN—((S)-1-((3aS,6S,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxobutan-2-yl)-4-(4-methylpiperazin-1-yl)benzamideN—((S)-1-((3aS,6S,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxobutan-2-yl)-4-(4-ethylpiperazin-1-yl)benzamideN—((S)-1-((3aS,6S,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxobutan-2-yl)-4-(4-propylpiperazin-1-yl)benzamideN—((S)-1-((3aS,6S,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxobutan-2-yl)-4-(4-isopropylpiperazin-1-yl)benzamideN—((S)-1-((3aS,6S,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxobutan-2-yl)-4-(4-(2-methoxyethyl)piperazin-1-yl)benzamideN—((S)-1-((3aS,6S,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxobutan-2-yl)-4-(4-cyclopropylpiperazin-1-yl)benzamideN—((S)-1-((3aS,6S,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxobutan-2-yl)-4-(4-cyclobutylpiperazin-1-yl)benzamideN—((S)-1-((3aS,6S,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxobutan-2-yl)-4-(1-propylpiperidin-4-yl)benzamideN—((S)-1-((3aS,6S,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxobutan-2-yl)-4-(1-cyclopropylpiperidin-4-yl)benzamideN—((S)-1-((3aS,6S,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxobutan-2-yl)-4-(1-cyclobutylpiperidin-4-yl)benzamideN—((S)-1-cyclopentyl-2-((3aS,6S,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-methylpiperazin-1-yl)benzamideN—((S)-1-cyclopentyl-2-((3aS,6S,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-ethylpiperazin-1-yl)benzamideN—((S)-1-cyclopentyl-2-((3aS,6S,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-propylpiperazin-1-yl)benzamideN—((S)-1-cyclopentyl-2-((3aS,6S,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-isopropylpiperazin-1-yl)benzamideN—((S)-1-cyclopentyl-2-((3aS,6S,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-(2-methoxyethyl)piperazin-1-yl)benzamideN—((S)-1-cyclopentyl-2-((3aS,6S,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-cyclopropylpiperazin-1-yl)benzamide4-(4-cyclobutylpiperazin-1-yl)-N—((S)-1-cyclopentyl-2-((3aS,6S,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)benzamideN—((S)-1-cyclopentyl-2-((3aS,6S,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(1-propylpiperidin-4-yl)benzamideN—((S)-1-cyclopentyl-2-((3aS,6S,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(1-cyclopropylpiperidin-4-yl)benzamide4-(1-cyclobutylpiperidin-4-yl)-N—((S)-1-cyclopentyl-2-((3aS,6S,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)benzamideN—((S)-1-cyclohexyl-2-((3aS,6S,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-methylpiperazin-1-yl)benzamideN—((S)-1-cyclohexyl-2-((3aS,6S,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-ethylpiperazin-1-yl)benzamideN—((S)-1-cyclohexyl-2-((3aS,6S,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-propylpiperazin-1-yl)benzamideN—((S)-1-cyclohexyl-2-((3aS,6S,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-isopropylpiperazin-1-yl)benzamideN—((S)-1-cyclohexyl-2-((3aS,6S,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-(2-methoxyethyl)piperazin-1-yl)benzamideN—((S)-1-cyclohexyl-2-((3aS,6S,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-cyclopropylpiperazin-1-yl)benzamide4-(4-cyclobutylpiperazin-1-yl)-N—((S)-1-cyclohexyl-2-((3aS,6S,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)benzamideN—((S)-1-cyclohexyl-2-((3aS,6S,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(1-methylpiperidin-4-yl)benzamideN—((S)-1-cyclohexyl-2-((3aS,6S,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(1-ethylpiperidin-4-yl)benzamideN—((S)-1-cyclohexyl-2-((3aS,6S,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(1-propylpiperidin-4-yl)benzamideN—((S)-1-cyclohexyl-2-((3aS,6S,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(1-isopropylpiperidin-4-yl)benzamideN—((S)-1-cyclohexyl-2-((3aS,6S,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(1-(2-methoxyethyl)piperidin-4-yl)benzamideN—((S)-1-cyclohexyl-2-((3aS,6S,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(1-cyclopropylpiperidin-4-yl)benzamide4-(1-cyclobutylpiperidin-4-yl)-N—((S)-1-cyclohexyl-2-((3aS,6S,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)benzamideN—((S)-1-((3aS,6R,6aS)-6-hydroxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)-4-(4-propylpiperazin-1-yl)benzamideN—((S)-1-((3aS,6R,6aS)-6-hydroxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)-4-(4-isopropylpiperazin-1-yl)benzamide4-(4-cyclopropylpiperazin-1-yl)-N—((S)-1-((3aS,6R,6aS)-6-hydroxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)benzamide4-(4-cyclobutylpiperazin-1-yl)-N—((S)-1-((3aS,6R,6aS)-6-hydroxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)benzamide4-(1-cyclopropylpiperidin-4-yl)-N—((S)-1-((3aS,6R,6aS)-6-hydroxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)benzamide4-(1-cyclobutylpiperidin-4-yl)-N—((S)-1-((3aS,6R,6aS)-6-hydroxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)benzamideN—((S)-1-((3aS,6R,6aS)-6-hydroxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)-4-(4-propylpiperazin-1-yl)benzamideN—((S)-1-((3aS,6R,6aS)-6-hydroxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)-4-(4-isopropylpiperazin-1-yl)benzamide4-(4-cyclopropylpiperazin-1-yl)-N—((S)-1-((3aS,6R,6aS)-6-hydroxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)benzamide4-(4-cyclobutylpiperazin-1-yl)-N—((S)-1-((3aS,6R,6aS)-6-hydroxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)benzamide4-(1-cyclopropylpiperidin-4-yl)-N—((S)-1-((3aS,6R,6aS)-6-hydroxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)benzamide4-(1-cyclobutylpiperidin-4-yl)-N—((S)-1-((3aS,6R,6aS)-6-hydroxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)benzamide4-(4-ethylpiperazin-1-yl)-N-((2S,3S)-1-((3aS,6R,6aS)-6-hydroxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)benzamideN-((2S,3S)-1-((3aS,6R,6aS)-6-hydroxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)-4-(4-propylpiperazin-1-yl)benzamideN-((2S,3S)-1-((3aS,6R,6aS)-6-hydroxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)-4-(4-isopropylpiperazin-1-yl)benzamide4-(4-cyclopropylpiperazin-1-yl)-N-((2S,3S)-1-((3aS,6R,6aS)-6-hydroxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)benzamide4-(4-cyclobutylpiperazin-1-yl)-N-((2S,3S)-1-((3aS,6R,6aS)-6-hydroxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)benzamide4-(1-cyclopropylpiperidin-4-yl)-N-((2S,3S)-1-((3aS,6R,6aS)-6-hydroxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)benzamide4-(1-cyclobutylpiperidin-4-yl)-N-((2S,3S)-1-((3aS,6R,6aS)-6-hydroxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)benzamide4-(4-ethylpiperazin-1-yl)-N—((S)-1-((3aS,6R,6aS)-6-hydroxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxobutan-2-yl)benzamide((S)-1-((3aS,6R,6aS)-6-hydroxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxobutan-2-yl)-4-(4-propylpiperazin-1-yl)benzamideN—((S)-1-((3aS,6R,6aS)-6-hydroxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxobutan-2-yl)-4-(4-isopropylpiperazin-1-yl)benzamide4-(4-cyclopropylpiperazin-1-yl)-N—((S)-1-((3aS,6R,6aS)-6-hydroxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxobutan-2-yl)benzamide4-(4-cyclobutylpiperazin-1-yl)-N—((S)-1-((3aS,6R,6aS)-6-hydroxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxobutan-2-yl)benzamide4-(1-cyclopropylpiperidin-4-yl)-N—((S)-1-((3aS,6R,6aS)-6-hydroxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxobutan-2-yl)benzamide4-(1-cyclobutylpiperidin-4-yl)-N—((S)-1-((3aS,6R,6aS)-6-hydroxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxobutan-2-yl)benzamideN—((S)-1-cyclopentyl-2-((3aS,6R,6aS)-6-hydroxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-methylpiperazin-1-yl)benzamideN—((S)-1-cyclopentyl-2-((3aS,6R,6aS)-6-hydroxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-ethylpiperazin-1-yl)benzamideN—((S)-1-cyclopentyl-2-((3aS,6R,6aS)-6-hydroxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-propylpiperazin-1-yl)benzamideN—((S)-1-cyclopentyl-2-((3aS,6R,6aS)-6-hydroxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-isopropylpiperazin-1-yl)benzamideN—((S)-1-cyclopentyl-2-((3aS,6R,6aS)-6-hydroxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-(2-methoxyethyl)piperazin-1-yl)benzamideN—((S)-1-cyclopentyl-2-((3aS,6R,6aS)-6-hydroxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-cyclopropylpiperazin-1-yl)benzamide4-(4-cyclobutylpiperazin-1-yl)-N—((S)-1-cyclopentyl-2-((3aS,6R,6aS)-6-hydroxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)benzamideN—((S)-1-cyclopentyl-2-((3aS,6R,6aS)-6-hydroxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(1-propylpiperidin-4-yl)benzamideN—((S)-1-cyclopentyl-2-((3aS,6R,6aS)-6-hydroxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(1-isopropylpiperidin-4-yl)benzamideN—((S)-1-cyclopentyl-2-((3aS,6R,6aS)-6-hydroxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(1-cyclopropylpiperidin-4-yl)benzamide4-(1-cyclobutylpiperidin-4-yl)-N—((S)-1-cyclopentyl-2-((3aS,6R,6aS)-6-hydroxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)benzamideN—((S)-1-cyclohexyl-2-((3aS,6R,6aS)-6-hydroxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-methylpiperazin-1-yl)benzamideN—((S)-1-cyclohexyl-2-((3aS,6R,6aS)-6-hydroxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-ethylpiperazin-1-yl)benzamideN—((S)-1-cyclohexyl-2-((3aS,6R,6aS)-6-hydroxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-propylpiperazin-1-yl)benzamideN—((S)-1-cyclohexyl-2-((3aS,6R,6aS)-6-hydroxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-isopropylpiperazin-1-yl)benzamideN—((S)-1-cyclohexyl-2-((3aS,6R,6aS)-6-hydroxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-(2-methoxyethyl)piperazin-1-yl)benzamideN—((S)-1-cyclohexyl-2-((3aS,6R,6aS)-6-hydroxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-cyclopropylpiperazin-1-yl)benzamide4-(4-cyclobutylpiperazin-1-yl)-N—((S)-1-cyclohexyl-2-((3aS,6R,6aS)-6-hydroxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)benzamideN—((S)-1-cyclohexyl-2-((3aS,6R,6aS)-6-hydroxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(1-propylpiperidin-4-yl)benzamideN—((S)-1-cyclohexyl-2-((3aS,6R,6aS)-6-hydroxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(1-isopropylpiperidin-4-yl)benzamideN—((S)-1-cyclohexyl-2-((3aS,6R,6aS)-6-hydroxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(1-(2-methoxyethyl)piperidin-4-yl)benzamideN—((S)-1-cyclohexyl-2-((3aS,6R,6aS)-6-hydroxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(1-cyclopropylpiperidin-4-yl)benzamide4-(1-cyclobutylpiperidin-4-yl)-N—((S)-1-cyclohexyl-2-((3aS,6R,6aS)-6-hydroxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)benzamideN—((S)-1-((3aS,6R,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)-4-(4-methylpiperazin-1-yl)benzamide4-(4-ethylpiperazin-1-yl)-N—((S)-1-((3aS,6R,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)benzamideN—((S)-1-((3aS,6R,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)-4-(4-propylpiperazin-1-yl)benzamide4-(4-isopropylpiperazin-1-yl)-N—((S)-1-((3aS,6R,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)benzamide4-(4-(2-methoxyethyl)piperazin-1-yl)-N—((S)-1-((3aS,6R,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)benzamide4-(4-cyclopropylpiperazin-1-yl)-N—((S)-1-((3aS,6R,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)benzamide4-(4-cyclobutylpiperazin-1-yl)-N—((S)-1-((3aS,6R,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)benzamide4-(1-cyclopropylpiperidin-4-yl)-N—((S)-1-((3aS,6R,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)benzamide4-(1-cyclobutylpiperidin-4-yl)-N—((S)-1-((3aS,6R,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)benzamide4-(4-ethylpiperazin-1-yl)-N—((S)-1-((3aS,6R,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)benzamideN—((S)-1-((3aS,6R,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)-4-(4-propylpiperazin-1-yl)benzamide4-(4-isopropylpiperazin-1-yl)-N—((S)-1-((3aS,6R,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)benzamide4-(4-(2-methoxyethyl)piperazin-1-yl)-N—((S)-1-((3aS,6R,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)benzamide4-(4-cyclopropylpiperazin-1-yl)-N—((S)-1-((3aS,6R,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)benzamide4-(4-cyclobutylpiperazin-1-yl)-N—((S)-1-((3aS,6R,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)benzamide4-(1-cyclopropylpiperidin-4-yl)-N—((S)-1-((3aS,6R,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)benzamide4-(1-cyclobutylpiperidin-4-yl)-N—((S)-1-((3aS,6R,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)benzamideN-((2S,3S)-1-((3aS,6R,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)-4-(4-methylpiperazin-1-yl)benzamide4-(4-ethylpiperazin-1-yl)-N-((2S,3S)-1-((3aS,6R,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)benzamideN-((2S,3S)-1-((3aS,6R,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)-4-(4-propylpiperazin-1-yl)benzamide4-(4-isopropylpiperazin-1-yl)-N-((2S,3S)-1-((3aS,6R,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)benzamide4-(4-(2-methoxyethyl)piperazin-1-yl)-N-((2S,3S)-1-((3aS,6R,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)benzamide4-(4-cyclopropylpiperazin-1-yl)-N-((2S,3S)-1-((3aS,6R,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)benzamide4-(4-cyclobutylpiperazin-1-yl)-N-((2S,3S)-1-((3aS,6R,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)benzamide4-(1-ethylpiperidin-4-yl)-N-((2S,3S)-1-((3aS,6R,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)benzamideN-((2S,3S)-1-((3aS,6R,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)-4-(1-propylpiperidin-4-yl)benzamide4-(1-isopropylpiperidin-4-yl)-N-((2S,3S)-1-((3aS,6R,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)benzamide4-(1-cyclopropylpiperidin-4-yl)-N-((2S,3S)-1-((3aS,6R,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)benzamide4-(1-cyclobutylpiperidin-4-yl)-N-((2S,3S)-1-((3aS,6R,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)benzamideN—((S)-1-((3aS,6R,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxobutan-2-yl)-4-(4-methylpiperazin-1-yl)benzamide4-(4-ethylpiperazin-1-yl)-N—((S)-1-((3aS,6R,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxobutan-2-yl)benzamideN—((S)-1-((3aS,6R,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxobutan-2-yl)-4-(4-propylpiperazin-1-yl)benzamide4-(4-isopropylpiperazin-1-yl)-N—((S)-1-((3aS,6R,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxobutan-2-yl)benzamideN—((S)-1-((3aS,6R,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxobutan-2-yl)-4-(4-(2-methoxyethyl)piperazin-1-yl)benzamide4-(4-cyclopropylpiperazin-1-yl)-N—((S)-1-((3aS,6R,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxobutan-2-yl)benzamide4-(4-cyclobutylpiperazin-1-yl)-N—((S)-1-((3aS,6R,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxobutan-2-yl)benzamide4-(1-cyclopropylpiperidin-4-yl)-N—((S)-1-((3aS,6R,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxobutan-2-yl)benzamide4-(1-cyclobutylpiperidin-4-yl)-N—((S)-1-((3aS,6R,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxobutan-2-yl)benzamideN—((S)-1-cyclopentyl-2-((3aS,6R,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-methylpiperazin-1-yl)benzamideN—((S)-1-cyclopentyl-2-((3aS,6R,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-ethylpiperazin-1-yl)benzamideN—((S)-1-cyclopentyl-2-((3aS,6R,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-propylpiperazin-1-yl)benzamideN—((S)-1-cyclopentyl-2-((3aS,6R,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-isopropylpiperazin-1-yl)benzamideN—((S)-1-cyclopentyl-2-((3aS,6R,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-(2-methoxyethyl)piperazin-1-yl)benzamideN—((S)-1-cyclopentyl-2-((3aS,6R,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-cyclopropylpiperazin-1-yl)benzamide4-(4-cyclobutylpiperazin-1-yl)-N—((S)-1-cyclopentyl-2-((3aS,6R,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)benzamideN—((S)-1-cyclopentyl-2-((3aS,6R,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(1-cyclopropylpiperidin-4-yl)benzamide4-(1-cyclobutylpiperidin-4-yl)-N—((S)-1-cyclopentyl-2-((3aS,6R,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)benzamideN—((S)-1-cyclohexyl-2-((3aS,6R,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-methylpiperazin-1-yl)benzamideN—((S)-1-cyclohexyl-2-((3aS,6R,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-ethylpiperazin-1-yl)benzamideN—((S)-1-cyclohexyl-2-((3aS,6R,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-propylpiperazin-1-yl)benzamideN—((S)-1-cyclohexyl-2-((3aS,6R,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-isopropylpiperazin-1-yl)benzamideN—((S)-1-cyclohexyl-2-((3aS,6R,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-(2-methoxyethyl)piperazin-1-yl)benzamideN—((S)-1-cyclohexyl-2-((3aS,6R,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-cyclopropylpiperazin-1-yl)benzamide4-(4-cyclobutylpiperazin-1-yl)-N—((S)-1-cyclohexyl-2-((3aS,6R,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)benzamideN—((S)-1-cyclohexyl-2-((3aS,6R,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(1-ethylpiperidin-4-yl)benzamideN—((S)-1-cyclohexyl-2-((3aS,6R,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(1-propylpiperidin-4-yl)benzamideN—((S)-1-cyclohexyl-2-((3aS,6R,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(1-isopropylpiperidin-4-yl)benzamideN—((S)-1-cyclohexyl-2-((3aS,6R,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(1-cyclopropylpiperidin-4-yl)benzamide4-(1-cyclobutylpiperidin-4-yl)-N—((S)-1-cyclohexyl-2-((3aS,6R,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)benzamideN—((S)-1-((3aS,6R,6aR)-6-amino-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)-4-(4-propylpiperazin-1-yl)benzamideN—((S)-1-((3aS,6R,6aR)-6-amino-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)-4-(4-cyclopropylpiperazin-1-yl)benzamideN—((S)-1-((3aS,6R,6aR)-6-amino-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)-4-(4-cyclobutylpiperazin-1-yl)benzamideN-((2S,3S)-1-((3aS,6R,6aR)-6-amino-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)-4-(4-ethylpiperazin-1-yl)benzamideN-((2S,3S)-1-((3aS,6R,6aR)-6-amino-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)-4-(4-propylpiperazin-1-yl)benzamideN-((2S,3S)-1-((3aS,6R,6aR)-6-amino-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)-4-(4-isopropylpiperazin-1-yl)benzamideN-((2S,3S)-1-((3aS,6R,6aR)-6-amino-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)-4-(4-cyclopropylpiperazin-1-yl)benzamideN-((2S,3S)-1-((3aS,6R,6aR)-6-amino-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)-4-(4-cyclobutylpiperazin-1-yl)benzamideN—((S)-1-((3aS,6R,6aR)-6-amino-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxobutan-2-yl)-4-(4-propylpiperazin-1-yl)benzamideN—((S)-1-((3aS,6R,6aR)-6-amino-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxobutan-2-yl)-4-(4-cyclopropylpiperazin-1-yl)benzamideN—((S)-1-((3aS,6R,6aR)-6-amino-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxobutan-2-yl)-4-(4-cyclobutylpiperazin-1-yl)benzamideN—((S)-2-((3aS,6R,6aR)-6-amino-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-1-cyclopentyl-2-oxoethyl)-4-(4-propylpiperazin-1-yl)benzamideN—((S)-2-((3aS,6R,6aR)-6-amino-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-1-cyclopentyl-2-oxoethyl)-4-(4-cyclopropylpiperazin-1-yl)benzamideN—((S)-2-((3aS,6R,6aR)-6-amino-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-1-cyclopentyl-2-oxoethyl)-4-(4-cyclobutylpiperazin-1-yl)benzamideN—((S)-2-((3aS,6R,6aR)-6-amino-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-1-cyclohexyl-2-oxoethyl)-4-(4-ethylpiperazin-1-yl)benzamideN—((S)-2-((3aS,6R,6aR)-6-amino-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-1-cyclohexyl-2-oxoethyl)-4-(4-propylpiperazin-1-yl)benzamideN—((S)-2-((3aS,6R,6aR)-6-amino-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-1-cyclohexyl-2-oxoethyl)-4-(4-isopropylpiperazin-1-yl)benzamideN—((S)-2-((3aS,6R,6aR)-6-amino-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-1-cyclohexyl-2-oxoethyl)-4-(4-cyclopropylpiperazin-1-yl)benzamideN—((S)-2-((3aS,6R,6aR)-6-amino-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-1-cyclohexyl-2-oxoethyl)-4-(4-cyclobutylpiperazin-1-yl)benzamideN—((S)-1-((3aS,6R,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)-4-(4-methylpiperazin-1-yl)benzamideN—((S)-1-((3aS,6R,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)-4-(4-ethylpiperazin-1-yl)benzamideN—((S)-1-((3aS,6R,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)-4-(4-propylpiperazin-1-yl)benzamideN—((S)-1-((3aS,6R,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)-4-(4-isopropylpiperazin-1-yl)benzamideN—((S)-1-((3aS,6R,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)-4-(4-(2-methoxyethyl)piperazin-1-yl)benzamideN—((S)-1-((3aS,6R,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)-4-(4-cyclopropylpiperazin-1-yl)benzamideN—((S)-1-((3aS,6R,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)-4-(4-cyclobutylpiperazin-1-yl)benzamideN—((S)-1-((3aS,6R,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)-4-(1-propylpiperidin-4-yl)benzamideN—((S)-1-((3aS,6R,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)-4-(1-isopropylpiperidin-4-yl)benzamideN—((S)-1-((3aS,6R,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)-4-(1-(2-methoxyethyl)piperidin-4-yl)benzamideN—((S)-1-((3aS,6R,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)-4-(1-cyclopropylpiperidin-4-yl)benzamideN—((S)-1-((3aS,6R,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)-4-(1-cyclobutylpiperidin-4-yl)benzamideN—((S)-1-((3aS,6R,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)-4-(4-methylpiperazin-1-yl)benzamideN—((S)-1-((3aS,6R,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)-4-(4-ethylpiperazin-1-yl)benzamideN—((S)-1-((3aS,6R,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)-4-(4-propylpiperazin-1-yl)benzamideN—((S)-1-((3aS,6R,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)-4-(4-isopropylpiperazin-1-yl)benzamideN—((S)-1-((3aS,6R,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)-4-(4-(2-methoxyethyl)piperazin-1-yl)benzamideN—((S)-1-((3aS,6R,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)-4-(4-cyclopropylpiperazin-1-yl)benzamideN—((S)-1-((3aS,6R,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)-4-(4-cyclobutylpiperazin-1-yl)benzamideN—((S)-1-((3aS,6R,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)-4-(1-propylpiperidin-4-yl)benzamideN—((S)-1-((3aS,6R,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)-4-(1-cyclopropylpiperidin-4-yl)benzamideN—((S)-1-((3aS,6R,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)-4-(1-cyclobutylpiperidin-4-yl)benzamideN-((2S,3S)-1-((3aS,6R,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)-4-(4-methylpiperazin-1-yl)benzamideN-((2S,3S)-1-((3aS,6R,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)-4-(4-ethylpiperazin-1-yl)benzamideN-((2S,3S)-1-((3aS,6R,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)-4-(4-propylpiperazin-1-yl)benzamideN-((2S,3S)-1-((3aS,6R,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)-4-(4-isopropylpiperazin-1-yl)benzamideN-((2S,3S)-1-((3aS,6R,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)-4-(4-(2-methoxyethyl)piperazin-1-yl)benzamideN-((2S,3S)-1-((3aS,6R,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)-4-(4-cyclopropylpiperazin-1-yl)benzamideN-((2S,3S)-1-((3aS,6R,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)-4-(4-cyclobutylpiperazin-1-yl)benzamideN-((2S,3S)-1-((3aS,6R,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)-4-(1-methylpiperidin-4-yl)benzamideN-((2S,3S)-1-((3aS,6R,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)-4-(1-ethylpiperidin-4-yl)benzamideN-((2S,3S)-1-((3aS,6R,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)-4-(1-propylpiperidin-4-yl)benzamideN-((2S,3S)-1-((3aS,6R,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)-4-(1-isopropylpiperidin-4-yl)benzamideN-((2S,3S)-1-((3aS,6R,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)-4-(1-(2-methoxyethyl)piperidin-4-yl)benzamideN-((2S,3S)-1-((3aS,6R,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)-4-(1-cyclopropylpiperidin-4-yl)benzamideN-((2S,3S)-1-((3aS,6R,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)-4-(1-cyclobutylpiperidin-4-yl)benzamideN—((S)-1-((3aS,6R,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxobutan-2-yl)-4-(4-methylpiperazin-1-yl)benzamideN—((S)-1-((3aS,6R,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxobutan-2-yl)-4-(4-ethylpiperazin-1-yl)benzamideN—((S)-1-((3aS,6R,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxobutan-2-yl)-4-(4-propylpiperazin-1-yl)benzamideN—((S)-1-((3aS,6R,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxobutan-2-yl)-4-(4-isopropylpiperazin-1-yl)benzamideN—((S)-1-((3aS,6R,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxobutan-2-yl)-4-(4-(2-methoxyethyl)piperazin-1-yl)benzamideN—((S)-1-((3aS,6R,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxobutan-2-yl)-4-(4-cyclopropylpiperazin-1-yl)benzamideN—((S)-1-((3aS,6R,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxobutan-2-yl)-4-(4-cyclobutylpiperazin-1-yl)benzamideN—((S)-1-((3aS,6R,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxobutan-2-yl)-4-(1-propylpiperidin-4-yl)benzamideN—((S)-1-((3aS,6R,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxobutan-2-yl)-4-(1-cyclopropylpiperidin-4-yl)benzamideN—((S)-1-((3aS,6R,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxobutan-2-yl)-4-(1-cyclobutylpiperidin-4-yl)benzamideN—((S)-2-((3aS,6R,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-1-cyclopentyl-2-oxoethyl)-4-(4-methylpiperazin-1-yl)benzamideN—((S)-2-((3aS,6R,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-1-cyclopentyl-2-oxoethyl)-4-(4-ethylpiperazin-1-yl)benzamideN—((S)-2-((3aS,6R,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-1-cyclopentyl-2-oxoethyl)-4-(4-propylpiperazin-1-yl)benzamideN—((S)-2-((3aS,6R,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-1-cyclopentyl-2-oxoethyl)-4-(4-isopropylpiperazin-1-yl)benzamideN—((S)-2-((3aS,6R,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-1-cyclopentyl-2-oxoethyl)-4-(4-(2-methoxyethyl)piperazin-1-yl)benzamideN—((S)-2-((3aS,6R,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-1-cyclopentyl-2-oxoethyl)-4-(4-cyclopropylpiperazin-1-yl)benzamideN—((S)-2-((3aS,6R,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-1-cyclopentyl-2-oxoethyl)-4-(4-cyclobutylpiperazin-1-yl)benzamideN—((S)-2-((3aS,6R,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-1-cyclopentyl-2-oxoethyl)-4-(1-propylpiperidin-4-yl)benzamideN—((S)-2-((3aS,6R,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-1-cyclopentyl-2-oxoethyl)-4-(1-cyclopropylpiperidin-4-yl)benzamideN—((S)-2-((3aS,6R,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-1-cyclopentyl-2-oxoethyl)-4-(1-cyclobutylpiperidin-4-yl)benzamideN—((S)-2-((3aS,6R,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-1-cyclohexyl-2-oxoethyl)-4-(4-methylpiperazin-1-yl)benzamideN—((S)-2-((3aS,6R,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-1-cyclohexyl-2-oxoethyl)-4-(4-ethylpiperazin-1-yl)benzamideN—((S)-2-((3aS,6R,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-1-cyclohexyl-2-oxoethyl)-4-(4-propylpiperazin-1-yl)benzamideN—((S)-2-((3aS,6R,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-1-cyclohexyl-2-oxoethyl)-4-(4-isopropylpiperazin-1-yl)benzamideN—((S)-2-((3aS,6R,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-1-cyclohexyl-2-oxoethyl)-4-(4-(2-methoxyethyl)piperazin-1-yl)benzamideN—((S)-2-((3aS,6R,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-1-cyclohexyl-2-oxoethyl)-4-(4-cyclopropylpiperazin-1-yl)benzamideN—((S)-2-((3aS,6R,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-1-cyclohexyl-2-oxoethyl)-4-(4-cyclobutylpiperazin-1-yl)benzamideN—((S)-2-((3aS,6R,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-1-cyclohexyl-2-oxoethyl)-4-(1-methylpiperidin-4-yl)benzamideN—((S)-2-((3aS,6R,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-1-cyclohexyl-2-oxoethyl)-4-(1-ethylpiperidin-4-yl)benzamideN—((S)-2-((3aS,6R,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-1-cyclohexyl-2-oxoethyl)-4-(1-propylpiperidin-4-yl)benzamideN—((S)-2-((3aS,6R,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-1-cyclohexyl-2-oxoethyl)-4-(1-isopropylpiperidin-4-yl)benzamideN—((S)-2-((3aS,6R,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-1-cyclohexyl-2-oxoethyl)-4-(1-(2-methoxyethyl)piperidin-4-yl)benzamideN—((S)-2-((3aS,6R,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-1-cyclohexyl-2-oxoethyl)-4-(1-cyclopropylpiperidin-4-yl)benzamideN—((S)-2-((3aS,6R,6aS)-6-azido-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-1-cyclohexyl-2-oxoethyl)-4-(1-cyclobutylpiperidin-4-yl)benzamide.16. A pharmaceutical or veterinary composition comprising a compoundaccording to claim 1 and a pharmaceutically acceptable or veterinarilyacceptable diluent, excipient and/or carrier.
 17. A process forpreparing a pharmaceutical or veterinary composition, said processcomprising admixing a compound according to claim 1 with apharmaceutically acceptable or veterinarily acceptable diluent,excipient and/or carrier.
 18. A compound according to claim 1 which isselected from the following:N—((S)-1-((3aS,6S,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)-4-(4-methylpiperazin-1-yl)benzamide;N—((S)-1-((3aS,6S,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)-4-(4-methylpiperazin-1-yl)benzamide;N—((S)-1-((3aS,6R,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)-4-(4-methylpiperazin-1-yl)benzamide;4-(4-ethylpiperazin-1-yl)-N—((S)-1-((3aS,6S,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)benzamide;4-(4-ethylpiperazin-1-yl)-N—((S)-1-((3aS,6S,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)benzamide;4-(4-ethylpiperazin-1-yl)-N—((S)-1-((3aS,6R,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)benzamide;4-(4-ethylpiperazin-1-yl)-N—((S)-1-((3aS,6R,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)benzamide;N—((S)-1-((3aS,6S,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)-4-(4-propylpiperazin-1-yl)benzamide;N—((S)-1-((3aS,6S,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)-4-(4-propylpiperazin-1-yl)benzamide;N—((S)-1-((3aS,6R,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)-4-(4-propylpiperazin-1-yl)benzamide;N—((S)-1-((3aS,6R,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)-4-(4-propylpiperazin-1-yl)benzamide;4-(4-isopropylpiperazin-1-yl)-N—((S)-1-((3aS,6R,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)benzamide;N—((S)-1-((3aS,6S,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)-4-(4-(2-methoxyethyl)piperazin-1-yl)benzamide;N—((S)-1-((3aS,6R,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)-4-(1-propylpiperidin-4-yl)benzamide;N—((S)-1-cyclopentyl-2-((3aS,6S,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-methylpiperazin-1-yl)benzamide;N—((S)-1-cyclopentyl-2-((3aS,6S,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-ethylpiperazin-1-yl)benzamide;andN—((S)-1-cyclopentyl-2-((3aS,6R,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-ethylpiperazin-1-yl)benzamide.19. A compound according to claim 18 which is selected from thefollowing:N—((S)-1-((3aS,6S,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)-4-(4-methylpiperazin-1-yl)benzamide;N—((S)-1-((3aS,6S,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)-4-(4-propylpiperazin-1-yl)benzamide;4-(4-isopropylpiperazin-1-yl)-N—((S)-1-((3aS,6R,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)benzamide;N—((S)-1-cyclopentyl-2-((3aS,6S,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-methylpiperazin-1-yl)benzamide;N—((S)-1-cyclopentyl-2-((3aS,6S,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-ethylpiperazin-1-yl)benzamide;andN—((S)-1-cyclopentyl-2-((3aS,6R,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-ethylpiperazin-1-yl)benzamide.